Chemistry @ Cambridge

Department of biennial report 2012 Edited and designed by Sarah Houlton Photographs: Nathan Pitt and Caroline Hancox

Printed by Callimedia, Colchester Published by the Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW. Opinions are not necessarily those of the editor, the department, or the university Reluctant reactions

Academic staff An introduction to Christopher Abell Ali Alavi Stuart Althorpe Cambridge Chemistry Shankar Balasubramanian Nick Bampos Paul Barker Ian Baxendale Daniel Beauregard Andreas Bender Robert Best Peter Bond Sally Boss Jason Chin Alessio Ciulli Stuart Clarke Aron Cohen Graeme Day Christopher Dobson Melinda Duer Stephen Elliott Daan Frenkel Matthew Gaunt Robert Glen Jonathan Goodman Clare Grey Neil Harris Laura Itzhaki Sophie Jackson David Jefferson This Biennial Report is designed to give themes: chemistry of health, chemistry Stephen Jenkins a brief introduction to the Chemistry for sustainability, and chemistry for Bill Jones Department of the University of novel materials. Rod Jones Cambridge. Our department has a long On these topics, we engage in open history, yet our national and interna - collaboration with national and interna - Markus Kalberer tional position is not determined by our tional partners in academia, industry James Keeler past but by our current perfor - and government. mance. Just over 50 research groups We are fortunate to attract some of Tuomas Knowles form the core of the department. They the brightest and the best students – Finian Leeper deliver the research and the teaching both nationally and internationally. We that have given the department its posi - aim to provide them with the very best Steven Ley tion among the very best in the world. undergraduate teaching that will chal - Deborah Longbottom There are many ways to quantify our lenge them to excel in whatever they do. Mark Miller strength, such as our top ranking in the In this biennial report, we highlight a Jonathan Nitschke 2008 UK Research Assessment Exercise, small fraction of the exciting research William Nolan or the fact that nine out of 20 professors that is going on in the department. are Fellows of the Royal Society. These examples share one important Ian Paterson However, in the end, our success is feature with the much larger number John Pyle measured by the recognition that we of research projects that are not Erwin Reisner receive from former students, from our included here: they would not have Jeremy Sanders industrial partners, and from the world- been possible without the skills and Oren Scherman wide scientific community. A good dedication of our PhD students and measure of this recognition is the fact postdoctoral researchers. Michiel Sprik that 10 of our faculty have currently Much more information on our David Spring been awarded personal grants by the department, its research, its teaching Sergei Taraskin European Research Council (ERC). and the people who make it happen, can Michele Vendruscolo Scientific excellence and independ - be found by visiting our website at David Wales ence are at the basis of our research www.ch.cam.ac.uk. effort. But with excellence comes socie - Andrew Wheatley tal responsibility. Our faculty members Daan Frenkel Paul Wood are keenly aware of the great challenges Head of Department Peter Wothers facing the world, and have therefore June 2012 Dominic Wright chosen to collaborate on three strategic

www.ch.cam.ac.uk 1 News Chemical science at Cambridge: towards a healthy and sustainable future Over the past 150 years, chemistry has contributed to the applications in healthcare, agriculture, energy and consumer products. transformation of the world in which we live. Modern industry, We aim to maintain key chemical healthcare, nutrition and energy needs build on a sustained effort expertise, both experimental and theoret - ical, at the heart of our multi-disciplinary in chemical research and development. Chemical research has research activities. In parallel, we will been important for the creation of the modern society, and it will expand our translational research to pro - become even more important as we address the big issues that mote collaborative initiatives, both in aca - demia and with industry. We will: confront the world’s population today and in the future. I Strengthen or create interdisciplinary research institutes that provide state- of-the-art infrastructure, equipment The scope and depth of chemical At present, research interest groups and high-level technical support; research will need to be expanded sub - have been formed with a focus on the I Develop our partnership with indus - stantially, and in a way that transcends following five themes: biology, materi - try, with our global partners and traditional boundaries between disci - als chemistry, physical chemistry, syn - with major sponsors of research; plines. Here at Cambridge, the chem - thetic chemistry, and theory, modelling I Prioritise our resources and identify istry department has embraced this and informatics. opportunities for the development of challenge, and will make pioneering key shared research facilities; contributions to science in the 21st cen - STRATEGIC COLLABORATIVE I Develop cross-disciplinary doctoral tury. We will engage with scientists in RESEARCH training centres. other academic fields, and partners out - The research interest groups collaborate side academia, to ensure we maximise on a number of strategic themes. SUPPORTING RESEARCH LEADERS the societal impact of our research. Chemistry of health. Chemical sci - The best way to deliver our vision is to ence has a key role to play in improving have the best people, and support them to OUR DELIVERY PLAN the health of the world’s population. We do the best research. We will maintain an Our vision and delivery plan outlines aim to advance the understanding of environment for innovative research and how we will develop, manage, commu - health and disease in a number of areas excellence by: nicate and apply our targeted research that are of global importance. These I Providing a world-leading research themes, while embracing scholarly inv - include ageing, cancer and infection. training environment that develops and es tigation and furthering education. The Sustainable energy, environment nurtures the skills of the next generation delivery of our vision will focus on the and climate. We will use our expertise of academic and industrial scientists; following fundamental principles: to tackle grand technical and intellec - I Appointing the best early- and mid- I Identification of key strategic tual challenges associated with develop - career scientists in exciting estab - research themes; ing sustainable future energy systems. lished and emerging areas of science; I Supporting research leaders; Innovative molecular and materials I Promoting a culture of equality and I Educating the next generation of design. We will transform the develop - diversity; scientists; ment and assembly of important func - I Supporting academics to take the I Industrial partnership and tional chemicals to produce new high- lead on collaborative projects; entrepreneurship; value products that will lead to novel I Providing mechanisms to facilitate I Communication of research; the management of large projects; I Management and feedback of I Engendering participation in depart - success. Our vision is to enhance our reputation as mental structures, forums and deci - sion-making bodies. The department envisages that chemical a world-class research institution that is science will provide the solutions for a recognised for its innovation, excellence EDUCATING THE NEXT GENERATION OF SCIENTISTS healthy, sustainable future. At the heart and discovery, and which attracts the best of this vision lies a blend of inventive The department is committed to provid - basic chemical research and innovative students and staff worldwide. ing a stimulating environment for its stu - collaborative strategic themes that form dents and postdoctoral researchers that an outline for the next 10 years of We aspire to values that are based on will enable them to work on today’s scien - research at Cambridge. the highest professional and academic tific challenges and equip them to address societal challenges of the future. We aim BASIC CHEMICAL RESEARCH standards in terms of personal growth to achieve this by: The department of chemistry hosts and satisfaction offered to our staff and I Training the next generation of more than 50 research groups that chemical scientists for both academia cover a wide spectrum of chemical sci - students; growth and excellence in what and industry; ences. In 2010, the department took the we do; teamwork that is based on respect; I Developing new doctoral training strategic decision to organise its programmes in collaboration with research into five areas that would trust and integrity; and innovation to our industrial partners and major encourage scientific interaction across deliver value to our research partners, stakeholders; I the department. Academics are encour - and to society. Providing postdoctoral researchers aged to participate in multiple research with an opportunity to develop into interest groups to foster collaboration. research leaders.

2 www.ch.cam.ac.uk Vision & strategy

INDUSTRIAL PARTNERSHIP AND the UK and global chemical We measure success through the: ENTREPRENEURSHIP sciences research base; I Academic, environmental and The department has a strong track I Embrace web-based communication societal impact; record of commercialising and licens - to provide a platform for broader I Economic impact, for example ing technologies that arise from basic dissemination of our research; through spin-out companies; research in the chemical sciences. It has I Increase our outreach activities with I Long-term and sustainable funding; also had great success in training grad - industry and not-for-profit sponsors I The destinations and careers of the uates and postgraduates for careers in of research through showcase people we train; industry. Many of our students become events and virtual institutes. I Quality and impact of the papers leaders in business and commerce. we publish; MANAGEMENT AND I Indicators of esteem, such as COMMUNICATION OF RESEARCH FEEDBACK OF SUCCESS prizes, awards and invited lectures. Our research ambitions can only be The department’s Research Strategy We will continue to monitor our success successful if there is broad societal sup - Committee is responsible for monitoring through external assessment that will port for chemical research, and if we the outcomes and impacts of our research include direct involvement of the can attract the best students. Both objec - and the success of our research strategy. Scientific Advisory Panel. tives imply that we must articulate the importance of our research by raising INCOME: RESEARCH GRANTS & CONTRACTS Grant income has remained stable over awareness of the benefits that accrue the past five years, reflecting to a large from our research, and the direct 2006-2007 2007-2008 2008-2009 2009-10 2010-11 extent that the department is working at impact on important societal, environ - £16.6m £18.1m £17.9m £15.6m £16.8m maximum capacity in the current space mental and economic needs. GRANTS AWARDED 2009 –12 by source & research area available. The department continues to We will publicise our important enjoy a sustainable spread of funders. research developments through all Charity 10% Theoretical & Atmospheric A fund-raising campaign is being aspects of the media, thereby ensuring computational science 10% launched to raise money for a new Research 17% that there is public dissemination of our councils 34% building focused on the chemistry of science. Specifically, we will: EC 19% Biological 23% I health. The building will create about Play a leading role in advocating Synthesis 28% 3300m 2 of vital additional space, and and influencing research policy; Government I Overseas 6% (including Royal Materials & enable us to build on and develop Ensuring that our staff support and Society) 15% physical 20% our chemistry in this important field, participate in forums that support Industry 16% right across the department.

Teaching Educating the next generation of chemists The aim of our undergraduate course is to enthuse and educate there teaching and enthusing the next generation of chemists. the next generation of top-flight chemists. We aim to do this by For some years now, we have had offering outstanding teaching in an excellent physical and intellec - teaching fellows in the department. These are members of the staff whose tual environment. The research excellence of the department focus is on undergraduate teaching, underpins and informs both the way we teach, and what we teach. rather than research. Over this period we have added two further teaching fel - Undergraduate numbers have remained imparted by a Cambridge education. lows, Sally Boss and Deborah Long - buoyant in recent years, with just over We continue to receive a significant bottom. Both are joint appointments 100 students taking the third-year number of exchange students from with colleges, which very much rein - course, and around 70 of these carrying around the world, many coming forces the vital link between college and on to the fourth year. We have more through the Erasmus scheme. These stu - university teaching. than 500 students taking first-year dents typically take parts of the third- or These appointments are a particularly chemistry, but because of the structure fourth-year course and often also clear expression of the department’s of the Natural Sciences course, this undertake a research project. Their pres - ongoing commitment to providing a includes students who are heading off ence and the valuable different perspec - very high standard of undergraduate to specialise in , materials sci - tives they bring help to remind us not education. ence or biology. that we are part of a worldwide chem - Many of our students seek place - About half of our graduates go on to istry community. ments and some kind of research expe - take research degrees either here in rience over the summer vacations. There Cambridge or at other top universities. FUTURE CAREERS is no doubt about the value of such The other half head off into general In the past, few of our students have experience, particularly in the latter graduate employment in areas such as gone into secondary school teaching, parts of the course and as a run-up to accountancy, patent work, the law, but this has changed over the past few starting their final year research project. financial services – in fact in just about years. The increasing status and higher Funding for such placements is always a any role one might think of. One recent profile of a career in teaching, plus a problem, but a new initiative from the graduate is even pursuing a career as a wider range of options for entering the department’s Corporate Associates fashion designer! profession such as the graduate teacher scheme has provided a significant Our graduates remain in demand scheme, has made this a more attractive amount of support, allowing many even in the current climate, and we take option. It is surely a good thing that more students to reap the benefits of this as a tribute to the special qualities Cambridge chemistry graduates are out summer placements.

www.ch.cam.ac.uk 3 News Prizes & awards Christian Doppler Lab Perhaps the best confirmation of the great science that goes on Erwin Reisner, his in the department is the range of prizes our chemists are group and guests awarded from many different societies and organisations. at the lab’s official In the past two years, many of our chemists, from the estab - opening lished, senior member of the department to those just starting out on their independent careers, have been recognised. These include: Andreas Bender , European Federation for Medicinal Chemistry Young Medicinal Chemist in Academia prize, 2010; Innovation Prize of the German Pharmaceutical and Chemical Societies, 2011; Molecular Graphics and Modelling Society’s Silver Jubilee award, 2011; Robert Best , RSC Marlow Award, 2012; The department’s Christian Doppler lab - National Foundation for Research, , RSC Khorana Prize, 2010; oratory for Sustainable SynGas Technology and Development, and Daan Frenkel , RSC and Biophysical Chemistry Chemistry had its official opening in OMV Group, the Austrian-headquar - Award, 2010; Joseph O. Hirschfelder Prize, 2011; RSC Spiers April 2012. tered international oil and gas company, Memorial Award, 2012; Headed up by Erwin Reisner, the for the next seven years. Clare Grey , RSC John Jeyes Award, 2010; Ampere Prize, 2010; state-of-the-art lab is focused on ‘The new laboratory aims to develop Kavli Medal, 2011; research into using sunlight to power the basic principles to allow for a Tuomas Knowles , RSC Harrison-Meldola Memorial Prize, 2012; the sustainable conversion of carbon renewable production of syngas,’ Richard Lambert , ACS Langmuir Lectureship, 2010; dioxide and water into syngas. Reisner says. ‘Our long-term vision is a Steve Ley , Tetrahedron Prize, 2010; Swiss This high-energy gas mixture con - transition from a fossil-based to a sus - Paracelsus Prize, 2010; Royal Society Royal Medal, 2011; tains hydrogen and carbon monoxide, tainable carbon-based economy.’ Peter Murray-Rust , ACS Herman Skolnik award, 2012; and can be used to create liquid hydro - The main focus of the lab will be the Jonathan Nitschke , RSC Corday Morgan Medal, 2011; Dalton carbon fuels. It is also an important development of molecular catalysts, Transactions European/African Lectureship, 2011; RSC Cram feedstock in the petrochemical industry. which will then be integrated into Lehn Pedersen Prize, 2012; The lab is being funded jointly by the nano-structured materials for syngas David Spring , RSC Norman Heatley Award, 2011; Austrian Christian Doppler Research generation. Ultimately, the aim is that Dominic Wright , RSC Main Group Chemistry award, 2012. Association, Federal Ministry of this will enable small-scale devices that Several department members have won best poster and Economy, Family and Youth, the make solar syngas to be assembled. presentation prizes at prestigious conferences, including: Mark Eddleston , a PhD student with Bill Jones, won the best talk in the Young Crystallographers’ session at the British Personal research grants Crystallographic Association’s 2010 meeting Frederic Blanc , a research fellow with Clare Grey, won the A department cannot function without Matthew Gaunt , Markus Kalberer , best poster prize at the 18th International Conference on funding, and several individual grant Jonathan Nitschke and David Solid-State Ionics in 2011 awards have been particularly notable. Spring, joining existing awardee Sean Hudson , a PhD student with , won best In the past couple of years, these per - Oren Scherman ; poster prize at the 2010 RSC symposium on the medicinal sonal grants have included: I EPSRC Leadership Fellowships to chemistry of tropical diseases I ERC Advanced Investigator Grants Ali Alavi , Matthew Gaunt and Gareth Lloyd , a postdoc with Bill Jones, won the CCDC to John Pyle , David Wales and Jonathan Nitschke ; Chemical Crystallography Prize for Younger Scientists in 2011. Dom inic Wright , joining existing I EPSRC Established Career Best poster prizes at the Lorne conference in Australia were awardees Daan Frenkel and Fellowship to David Spring ; won by Tim Guilliams from Chris Dobson’s group in 2010, Clare Grey ; I Jane Clarke ’s Welcome Trust Senior and Nicole Lim from Sophie Jackson’s group in 2012. I ERC Starting Investigator Grants to Research Fellowship was renewed. Finally, several awards for teaching and outreach activities have also been received by members of the department: Corporate Associates Junior Faculty teaching awards to Ian Baxendale , Sally Boss and Felipe Garcia ; Sphere Fluidics spin-out Deborah Longbottom , Pilkington Teaching Prize; Peter Wothers , RSC President’s Award, 2011. Over the years, a number of spin-out The company was set up in 2010 companies have been formed by and focuses on the picodroplet technol - Cambridge chemists with the aim of ogy developed by Chris Abell and Fellowships commercialising their science. Wilhelm Huck that allows researchers to One of the greatest honours a British scientist can receive is to Several have been real successes, such carry out large numbers of simultane - be made a Fellow of the Royal Society. In 2011, Clare Grey as DNA sequencing company Solexa, set ous reactions contained within small was made a fellow; in 2012, the honour was bestowed on up by Shankar Balasubramanian and aqueous droplets just a fraction of a mil - both Shankar Balasubramanian and David Klenerman . David Klenerman, and Cambridge limetre in size. Other organisations have also given Cambridge chemists Display Technology, which built on the When the droplets are merged with fellowships. Shankar Balasubramanian was made a Fellow of work of the Melville Laboratory under others containing, say, a specific chemi - the Academy of Medical Sciences in 2011, and Chris Abell its former director, Andrew Holmes. cal reagent, they act as miniature reac - also became a Fellow in 2012. And Chris Dobson was made The latest Cambridge chemistry spin- tion chambers. a Fellow of the Academia Europaea in 2011. out company, Sphere Fluidics, has The technology has potential uses in John Pyle became a Fellow of the American Geophysical gained funding from the Royal Society many different fields. These include Union in 2011, while Bill Jones was elected as an inaugural Enterprise Fund. This is in addition to analysing and isolating cell types, bio - Fellow of the Learned Society of Wales. the seed funding it received from the marker discovery in small volumes, and And both Shankar Balasubramanian and Jane Clarke were university’s Discovery Fund. It has also even carrying out molecular labelling made Members of the European Molecular Biology signed a research collaboration with a and separation using proprietary cata - Organisation in 2012. major pharmaceutical company. lysts and conditions.

4 www.ch.cam.ac.uk Highlights Todd-Hamied Laboratory The new Todd-Hamied Laboratory was Once the complex decontamination officially opened in August 2011. The was complete, the transformation from lab is home to the group of Geoffrey an abandoned and dangerous space Moorhouse Gibson professor Clare Grey. could begin. The Todd-Hamied Lab - It was refurbished with the generous oratory is now a modern space where assistance of Yusuf Hamied, and named the group is carrying out important in honour of his supervisor and mentor work on energy storage and conversion Lord Todd, Nobel laureate and former materials for use in the next generation head of department at Cambridge. of batteries and fuel cells. The new space represents a significant At the opening, Grey spoke on her transformation – and a lot of time, work work using NMR spectroscopy to aid the and effort. This area of the basement design of next generation of batteries used to be home to Alfie Maddock and fuel cells, Melinda Duer gave a pres - whose work on radiochemistry left it entation on the use of solid state NMR to heavily contaminated with radioactive study tissues, postdoc Elodie Salager gave protactinium. a talk about NMR crystallography, and Before any refurbishment could take visiting speaker Chris topher Pickard place, the whole area had to be decon - from UCL spoke about his work on taminated. This problem was com - structure prediction and NMR shift cal - pounded by the presence of asbestos. culations from first principles. Clare Grey shows Yusuf Hamied around the new laboratory Lennard-Jones Centre opens The Lennard Jones Centre for lecture theatre, Haroon Ahmed, former Computational Materials Science was Master of Corpus Christi and emeritus officially opened in December 2011. It professor of microelectronics in the is named after Sir John Lennard-Jones, Cavendish, gave a brief biographical who was the first professor of theoreti - sketch of Lennard-Jones, and described cal chemistry in Cambridge, and also the early history of computing in the first director of the mathematical Cambridge. laboratory where the basis was laid for Volker Heine was also made the cen - all subsequent ‘machine computing’ in tre’s first honorary member for his sem - Cambridge. Its aim is to develop initia - inal contributions to the field of elec - tives that will foster teaching and tronic structure calculations. He also research on all aspects of computational gave an autobiographical account of the materials science. development of computational materi - Volker Heine, the centre’s first honorary member, at the opening At the opening, held in the Unilever als science at the Cavendish.

Cambridge –Elan Centre for Research A visit from President Barroso Innovation and Drug Discovery A new centre dedicated to research into rodegenerative diseases. As well as look - innovative therapies for Alzheimer’s and ing for novel compounds, the aim is Parkinson’s diseases is being established for the centre to characterise the funda - in the department. mental physico-chemical mechanisms The Irish-headquartered pharmaceu - by which they alter the behaviour of tical company Elan will invest $10 mil - proteins associated with neurodegener - lion over the first five years of the initial ative disorders. 10-year collaboration. Chris Dobson, Michele Vendruscolo The new Cambridge–Elan Centre for and Tuomas Knowles are all involved in Research Innovation and Drug Disc- the centre. ‘The department, and indeed overy will provide an interdisciplinary the university, is very keen on the ven - environment to enable translational ture, and on the opportunities that exist research. The aim is to discover novel to build on it for the future,’ Dobson says. The department had a distinguished President Barroso compounds that can alter the behaviour ‘The process of bringing together political visitor in February 2011 – José (second left) poses of proteins associated with neurodegen - researchers at Cambridge and at Elan has Manuel Barroso, president of the in the department erative disorders, and which could be already created novel insights and European Commission. foyer with developed into new treatments. opportunities in drug discovery,’ he He was in Cambridge to give the university vice- Work on understanding the funda - adds. ‘The new centre builds on the suc - annual Alcuin lecture, speaking about chancellor Leszek mental molecular origins of these neu - cesses of this initial interaction to estab - the relationship between the British Borysiewicz, rogenerative disorders has been ongo - lish a long-term relationship to lead to nation and the European Institutions. Bill Jones and ing in Cambridge for more than a novel and effective therapies for the most Chemistry was asked to host him in the Jeremy Sanders decade, and Elan has a long-standing debilitating, costly and rapidly proliferat - Bristol-Myers Squibb lecture theatre, as interest in research in the field of neu - ing diseases in the modern world.’ it is the university’s largest.

www.ch.cam.ac.uk 5 Science Biology: the next big challenge for chemists

In the department, we have a particularly vibrant community of research groups with interests in biological molecules and systems. Research within the Biological RIG spans all areas of chemistry: from using state-of-the-art magnetic resonance techniques to study bone, combining the power of chemical synthesis and computational approaches to the development of new drugs and imaging agents, to understanding the molecular mechanisms by which proteins fold or misfold. Much of this is chemical biology, an emerging field in which scientific ideas and approaches developed by chemists are used to understand and manipulate biological systems in a highly controlled and specific manner. In addition to this, a number of research groups are taking inspiration from nature to develop new materials and devices. act as lead compounds in further drug development programmes. CHEMISTRY MEETS BIOLOGY Recently, they have been able to light up Above right: Shankar Balasubramanian ’s group Chemists have been interested in bio - proteins both in cells and whole ani - fragment is using similar chemical approaches to logical systems for many decades. mals for imaging applications. Ultim- molecules binding elucidate and manipulate the mecha - However, traditionally they have studied ately, these techniques have the poten - to a cytochrome nisms that control gene expression, isolated biological molecules in vitro , tial to provide a real-time molecular P450 enzyme from either transcription or translation. This sometimes in an environment very dif - description of complex biological Mycobacterium work has demonstrated that non- ferent from that found in vivo . As processes such as animal development tuberculosis, the canonical nucleic acid structures, such advances are made in many areas of and neural processing. bacterium as G-quadruplexes, may be associated chemistry, we have begun to bridge this responsible for TB with various cancers and are potential divide and now even have methods for MOLECULAR MEDICINE targets for small drug-like molecules. studying chemical processes in live cells The power of chemical synthesis to The group is also applying and devel - and organisms. construct reagents to both probe and oping chemical strategies to study epi - Melinda Duer and her group are control biological molecules and sys - genetic marks in the genome, some of developing solid-state NMR spec - tems is also illustrated by research in which have been shown to control gene troscopy techniques to investigate the many other groups whose focus is expression during development and in structure of the organic-inorganic inter - molecular medicine. cancer. As part of this programme of face in biominerals such as bone. This Chris Abell and Alessio Ciulli ’s work, the group has recently invented allows them to determine the structures groups, for example, are using frag - chemistry for sequencing 5-hydroxy - of biomolecules in their native tissues, ment-based screening methods that methyl cytosine in DNA at single base thus providing much better informa - were developed in the department to Below: structure of resolution, something that was previ - tion on the structure and function of identify small, drug-like molecules that the organic –inorganic ously not possible. these species in a living organism. can target proteins associated with dis - interface in biominerals As well as advances in spectroscopic eases such as TB and cancer. They also such as bone PROTEIN FOLDING, techniques, other groups are using MISFOLDING AND DISEASE novel chemistries and reagents to inves - collagen Proteins are not only the target of most tigate biological processes in vivo . therapeutic drugs but, as a result of mis - OH NHCOCH3 Finian Leeper ’s group is using unusual OH NHCOCH3 folding or misfunction, are themselves HO O HO O O O O glycosaminoglycan bio-orthogonal reactions, some of O the underlying cause of almost all dis - O O -OOC - OSO - OOC 3 OH which are the fastest yet reported, to OSO - ease states and conditions. 3 OH develop reagents for the imaging of In order to function, the large major - cancers in live animals. One such ity of our proteins need to fold into a reagent, tetra-acetyl N-azidoacetyl- mineral specific three-dimensional structure galactosamine, is able to link to tumour and failure of proteins to fold correctly, cells via their cell-surface glycan and is HO or remain folded, has been found to be OSO - HO 3 - OSO - COO 3 - a powerful imaging agent. COO O the origin of a wide variety of patho - O O glycosaminoglycan O O Jason Chin ’s group is also harnessing O O OH logical conditions, including cancer and O OH H3COCHN HO the power of chemistry to develop H3COCHN HO neurodegeneration. Chris Dobson innovative methods for studying bio - collagen ’s group has pioneered logical molecules and processes in vivo . the study of protein misfolding and

6 www.ch.cam.ac.uk Biological

established some of the fundamental principles that govern protein aggrega - tion and its associated toxicity. They have worked with many other groups in the department who have developed innovative experimental and theoretical methodologies to under - stand the molecular origins of protein misfolding diseases, particularly focus - ing on neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. David Klenerman ’s group has led the development of sensitive single-mole - cule spectroscopic methods to detect and characterise aggregated species both in solution and in the membrane study the pathways by which proteins Above: when technique to study algae for algal bio - of living cells. with complex structures fold produc - proteins misfold, fuel development and, along with Oren The group of Tuomas Knowles is tively in order to understand how diseases such as Scherman ’s group, they have recently developing physical tools to study pro - nature has solved some of the problems Alzheimer’s are developed a novel way to generate tein aggregation, and Michele associated with misfolding. the result microcapsules. This technology is also Vendruscolo’ s group has successfully Jane Clarke ’s group focuses on being further developed and used by applied state-of-the-art computational multi-domain proteins, Laura Itzhaki ’s the groups of both David Klenerman approaches to study and predict the group on repeat proteins which have a and Tuomas Knowles groups to study physico-chemical determinants of pro - modular architecture, while Sophie protein folding and misfolding. tein aggregation. Jackson ’s group studies an unusual set In collaboration with Sophie of proteins which have a knotted topol - TAKING INSPIRATION Jackson ’s group, they are investigating ogy. In all cases, computational methods FROM BIOLOGY how some of the body’s natural defence are used alongside experimental work Using chemical tools and methods to systems – molecular chaperones – deal in order to gain further detail of the interrogate and manipulate biological with misfolded and aggregated proteins complex processes involved. molecules and systems is the approach in vivo . Together, this extensive pro - The groups of Michele Vendruscolo , of many groups in the Biological RIG gramme of research aims to develop Robert Best and David Wales are all described above. Other groups, how - new and rational therapeutic strategies developing and applying theoretical and ever, take their inspiration from nature, against many disease states. computational methodology to the and use it to create novel solutions The group of Jane Clarke also study protein folding and unfolding. to some of the pressing issues of the employs cutting-edge single-molecule 21st century. techniques to study the complex prob - DEVELOPING NEW Paul Barker ’s group, stimulated by lem of how multi-domain proteins METHODOLOGIES the wide variety of roles of haem in fold. Their recent work has established Many groups within the department biology and by the ability of biological that misfolding may be far more com - have been instrumental in pushing the systems to self assemble, is creating new mon than expected. boundaries of what is possible with biomaterials which can be used as elec - Laura Itzhaki ’s group, meanwhile, both computational and experimental tron carriers or transistors in molecular studies the misfolding (or in this case methods, and this is no better illustrated electronic devices. unfolding) of a different class of pro - than with the protein folding and mis - Erwin Reisner ’s group takes its inspi - teins which have a very distinctive folding studies described above. ration from the highly efficient architecture, including the ankyrin, Other groups are also making consid - Below left: visible processes by which nature harvests HEAT and ARM repeat proteins. These erable headway in other directions. light-driven H 2 energy from the sun, and is developing proteins also play an important role in Chris Abell runs a leading micro - production with novel chemistries and molecules to disease, in particular cancer, and droplets group, and this technology is an enzyme – generate devices which can address insights gained from the research are now being applied in a wide variety of nanoparticle some of the major issues associated being used to develop novel therapeutic research programmes within the hybrid system with energy and sustainability. strategies. Many of these groups also department. His group is using this Research into biological molecules and systems has grown considerably within the department in the past 10 years, providing both great strength and depth and making Cambridge a world leader in this area. Starting from and centred around collaborations within the department, research programmes in chemical biology, molecular medicine and molecular and cellular now extend across Cambridge, the UK and around the world. Our research is addressing many of the most important issues that are facing society today.

www.ch.cam.ac.uk 7 Research New materials: from energy to medicines

Modern materials chemistry is a wide-ranging topic and includes have resulted in discrete spherical cages exhibiting fullerene-like morphology. surfaces, interfaces, polymers, nanoparticles and nanoporous Recently, however, the group has materials, self assembly and biomaterials, with applications described a three-dimensional metal– organic framework based on the relevant to oil recovery and separation, catalysis, photovoltaics, fullerene units. These arrangements can fuel cells and batteries, crystallisation and pharmaceutical act as air-stable, responsive hosts for solvent and, potentially, gas molecules. formulation, gas sorption, energy, functional materials, – The {C 5(CN) 5 } anion – a five-mem - biocompatible materials, computer memory, and sensors. There bered aromatic ring decorated by five are several common themes that run across the RIG. Research is cyanide moieties – is the simplest mem - ber of the extremely rare family of five- carried out in energy production, storage and conversion; fold-symmetric nodes, and was chosen surfaces, crystals and catalysis; biomaterials; sensors and as the ligand. On crystallising this ligand with transducers; and self-assembling functional materials. sodium ions by slow vapour diffusion of ether in a nitromethane solution, an assembly of a highly solvated, highly MATERIALS FOR ENERGY A schematic metastable, three-dimensional metal– Clare Grey ’s group uses a range of ana - representation of organic framework was seen, directed lytical techniques to study the local the void structure by the solvent molecules. structure of a wide range of technolog - of a unit cell. Characterisation by X-ray diffraction ically important, but disordered, mate - Yellow spheres revealed that each ligand binds five rials and the role this local structure represent voids sodium centres through nearly linear plays in controlling the materials’ phys - inside D cages and CN–Na bonds. These, in turn, organise ical properties. The primary technique orange bars 1D into a coordination network compris - is nuclear magnetic resonance (NMR), channels running ing sodium–ligand pentagonal and which probes the local environment through T cages. hexagonal faces, making up units that around a particular nucleus, and is ideal The outline of one resemble fullerene moieties. The result - to study such materials. The key tools in D cage and two T ing MOF exhibits both discrete cavities this research are four solid state NMR cages are shown to and linear non-intersecting channels spectrometers, the most recent of illustrate the that run through the empty faces. which was installed in late 2011. There structural out in situ studies of lithium ion batter - Removal of the solvent molecules is one high field machine and three low, relationship to ies that capture the short-lived under mild conditions does not cause which reflects the breadth of research, Type I gas hydrates metastable phases which appear at vari - the MOF to collapse, but instead leads to with the low field machines particularly ous stages of battery cycling. These stud - a different morphology. The unsolvated suitable for paramagnetic samples. ies are carried out using a flexible plas - framework adopts a more densely Specially designed probes that can be tic bag battery, which is placed inside packed layered arrangement, favoured used inside the spectrometers enable the NMR spectrometer. Other equip - by π-stacking between the ligands, the materials to be studied. For exam - ment includes furnaces for high tem - in which the CN–Na bonds are no ple, one probe can reach very high tem - perature synthesis, glove box for han - longer linear. peratures – up to 700°C – which allows dling air/moisture sensitive com - invaluable information on phase trans - Clare and her pounds, and battery cyclers for electro - SELF-ASSEMBLED STRUCTURES formations and dynamics to be group in the new chemical studies. Jonathan Nitschke ’s group is investi - obtained. The group is also able to carry Todd-Hamied lab gating the self-assembly of complex, BUILDING POROUS LATTICES functional structures from simple BASED ON FULLERENE molecular precursors and metal ions. Research in Dominic Wright ’s group One area of research is looking at focuses on metal–organic frameworks, molecular containers for greenhouse or MOFs. A myriad of these discrete and gases. Sulfur hexafluoride (SF 6) is the extended molecular assemblies have most potent greenhouse gas known, been prepared by chemists worldwide with a global warming potential more by coordinating metal ions to organic than 22,000 times that of CO 2, and a ligands, yet few have relied on planar lifetime in the atmosphere of up to components with a five-fold symmetry. 3000 years. Pentagonal or star-shaped building The group has designed a metal- blocks cannot tile into a planar surface organic capsule that is able to selectively without tilting or curving and, to date, encapsulate SF 6 from a mixture of the few metal–organic structures that atmospheric gases and store it under have been assembled with such ligands ambient conditions. The application of

8 www.ch.cam.ac.uk Materials

Right: the double- helical metal- containing polymers are good conductors of electricity, allowing them to function molecular wires

mild physical or chemical stimuli allows Above: a metal – the gas to be controllably released from organic capsule the host molecule, opening up the that is able opportunity for it to be recycled. to selectively type of complex behaviour found in both the capsule structure and the core Systems such as this could reduce the encapsulate SF 6 natural and man-made systems such as contents. However, it is still challenging amount of SF 6 that is released from from a mixture of neurons or transistors. to fabricate microcapsules in an effi - industrial processes, and could be highly atmospheric gases The new polymers are held together cient and scalable process without com - effective in abating global warming. by reversible imine and coordinative promising functionality and encapsula - Larger molecular containers to bonds and are capable of dynamic tion efficiency. encapsulate more complex guest mole - reconfiguration, allowing them to be The approach uses microdroplets, cules are also being developed. An built into self-healing materials – a frac - dispersed in oil as templates for build - example is a porphyrin-faced cube, ture in the polymer could be repaired ing supramolecular assemblies which which is able to selectively bind and simply by pressing the two broken form highly uniform microcapsules encapsulate large aromatic molecules edges of the material together. The with porous shells. The microdroplets such as coronene, C 60 and C 70 -C 84 . dynamic properties of these materials are loaded with copolymers, gold Other systems being investigated opens up the prospect of many new nanoparticles and small barrel-shaped include molecular containers, which applications. molecules called cucurbiturils, or CBs. might have applications as molecular These CBs act as miniature ‘handcuffs’, flasks for new types of reaction or in SUPRAMOLECULAR DESIGN OF bringing the materials together at the drug delivery, by delivering a specific NEW DELIVERY SYSTEMS oil-water interface. payload upon receipt of a specific A collaboration between the groups of The major advantage over current chemical signal. The dynamic assembly Chris Abell and Oren Scherman has methods is that all of the components of cages from subcomponents might resulted in the development of a new for the microcapsules are added at once, also be used to trap harmful molecules, technique for manufacturing ‘smart’ and they assemble instantaneously at preventing hydrophobic toxins or microcapsules in large quantities in a room temperature. chemical warfare agents from doing single step, using tiny droplets of water. The technique allows for a variety of damage by isolating them from the The encapsulation of materials for pro - cargoes to be efficiently loaded during environment. tection and phase separation has the formation of the microcapsules and Molecular wires represent another evolved into a major research focus in the dynamic supramolecular interac - fascinating area of research. Supra- biology, chemistry, nanotechnology and tions provide control over the porosity molecular polymers use reversible materials science. of the capsules and the timed release of bonds to hold their chains together, For microencapsulation applications their contents using stimuli such as resulting in striking dynamic properties it is important to accurately control light, pH and temperature. compared to traditional polymers joined together by inert covalent bonds. These ‘smart’ polymers can respond to changes in temperature, solvent, or the presence of chemical signals. The group has designed and synthe - sised new double-helical metal-contain - ing polymers that are good conductors of electricity, allowing them to function as molecular wires. The polymers’ prop - erties can be reversibly modified by application of stimuli such as heat resulting in a sol-to-gel transition. At the same time, the colour and lumines - cent intensity of the material changes in an interconnected way, generating the Cucubiturils act as miniature ‘handcuffs’, bringing materials together at the oil-water interface of atmospheric gases

www.ch.cam.ac.uk 9 Alumni Physical chemistry: the underpinning science

The primary focus of the Physical Chemistry RIG is the description and understanding of the properties of molecular systems in terms of physical principles. This knowledge impacts other branches of chemistry, and underlies many technological applications in rapidly developing areas such as climate change, nanotechnology and molecular medicine. Much of the research in the interest group is interdisciplinary, and the topics of study range from biomolecular systems to the atmosphere.

ENGINEERING ON A ing solar radiation. Aerosol composi - Right: Left- PLANETARY SCALE tions other than sulfuric acid could be and right-handed Geoengineering is the deliberate modi - used to dramatically increase the alaninate molecules fication of the earth’s climate system to amount of light scatter achieved on a per respectively form offset the global warming that results mass basis, thereby reducing the amount mirror-image left- from increasing greenhouse gases. of aerosol required for injection. and right-slanting Focusing on solar radiation manage - In Cambridge we are investigating patterns on a ment, or SRM, there are two futuristic the consequences of different aerosol copper surface. proposals: space mirrors to attenuate types on atmospheric chemistry and The images were the incoming solar radiation, and the dynamics. Groups in the Physical and obtained by deliberate injection of particles into the Atmospheric RIG are researching prop - scanning probe stratosphere, 15 –55km above the erties of proposed candidate particles microscopy, and earth’s surface. for deliberate injections. each separate Large volcanic eruptions provide a Laboratory experiments are per - feature is an natural analogue to aerosol injection. The formed by Markus Kalberer and alaninate molecule impact on the chemistry climate sys - most significant eruption in recent times Francis Pope to investigate chemical tem), and assess consequences of gen - was the 1991 eruption of Mount reactions involving particles that could eral solar radiation management on the Pinatubo in the Philippines, which led to potentially interfere with the chemistry atmospheric circulation. This forms part the formation of a sulfuric acid aerosol of the stratospheric ozone layer and of the due diligence required before any layer that reflected light and reduced the model calculations are performed by Below: perturbation such scheme could be utilised. average global temperature at the Earth’s John Pyle and Peter Braesicke to of the atmospheric surface by around 0.5°C for about two understand the natural analogue in the radiative budget HANDY SURFACE CHEMISTRY years. In addition to reflecting radiation context of ozone change attribution and the chemistry Ongoing research in the surface science this, sulfuric acid aerosol from Mount (the Mount Pinatubo eruption and its of the atmosphere group, led by Stephen Jenkins , promises Pinatubo was involved in ozone-destroy - by aerosol particles to reveal new insights into the ways in ing chemical reactions. injected into the which biologically important molecules, The ideal particle type for deliberate stratosphere such as amino acids, can self-organise stratospheric injections would max - into complex patterns when deposited imise the reflection of incoming solar onto a metal at sub-monolayer thickness. radiation, while at the same time min - The existence of these patterns has imising the stratospheric chemistry been recognised for some time, and the impact and any effect on stratospheric Cambridge group has long been at the circulation. Moreover, the particle forefront of progress in this field, but choice would ideally have minimal little knowledge has hitherto emerged impact on precipitation, ecosystems and about the fundamental processes of dif - human health. fusion, nucleation and growth that The economic viability of SRM by determine the long-range ordering of stratospheric particle injection will be molecules on the surface. dependent, among other criteria, on the Of particular interest is the link particle size and composition. between the chirality displayed by cer - To date, studies investigating this tain molecules – the property of coming scheme have focused upon the injection in either left-handed or right-handed of sulfuric acid or precursor gases to versions – and the handedness that this mimic the volcanic aerosols. However, imprints upon their global arrangement. the composition and size of volcanic Now, with the help of a substantial aerosol are far from optimal for reflect - grant from the US National Science

10 www.ch.cam.ac.uk Physical

Foundation (NSF) and the UK Engineering and Physical Sciences Research Council (EPSRC), the Cambridge team will join forces with the group of Jane Hinch at Rutgers University to pick apart the details of precisely how this imprinting happens. A unique combination of techniques will allow the researchers not only to address key questions about the struc - tures formed by molecules on the sur - face, but also to gain an understanding of the dynamic properties of these ultra-thin organic films. tinguish the single-colour monomers Above, from the and co-crystallisation strategies for tun - from oligomers as they will be dual- left: predicted ab ing materials properties. WARNING – MISFOLDING colour because they contain both red initio molecular Both groups have an active interest in PROTEINS AHEAD and blue-labelled monomers. structure, characterising the crystal structures of Physical chemistry techniques are Furthermore, it is also possible to esti - predicted crystal pharmaceutical molecules. A subject of increasingly applied outside of the area mate the size of the oligomers based on structure and particular interest is polymorphism – in which they were first developed, and their total fluorescence intensity. This observed crystal the ability of a molecule to crystallise in in particular several groups within the work has recently revealed that that clus - structure of a more than one crystal structure – which Physical Chemistry RIG are pioneering terin, a naturally occurring extracellular molecular cage, is particularly prevalent in pharmaceuti - the use of physical approaches in the chaperone, not only prevents oligomer showing the cals. The importance of identifying and study of the behaviour of biomolecules. formation when added in equimolar accessible surface characterising polymorphs when devel - Aberrant aggregation of proteins and ratios to monomeric amyloid- b1-40 pep - area in yellow oping a future drug relates to the peptides has been linked to a number of tides, but when oligomers are present, dependence of crucial properties such diseases. The most well-known of these clusterin binds them in long-lived com - as solubility and hardness on the crystal are a number of neurodegenerative dis - plexes and prevents their further growth structure; the occurrence of a new poly - orders such as Alzheimer’s disease, into fibrils or dissociation into morph can influence the processability, Parkinson’s disease, amyotrophic lateral monomers by this sequestration. bioavailability or shelf-life of a drug. sclerosis and Huntington’s disease. Each These results suggest a mechanism Combining computer-generated of these diseases is pathologically char - for the observations of abated cytotoxi - models of possible crystal structures acterised by the presence of large aggre - city and increased peptide degradation with diffraction data from transmission gates of a particular protein. in the presence of clusterin, and provide electron microscopy (TEM), the two In the case of Alzheimer’s disease, the a molecular basis for the genetic link groups have developed a novel characteristic protein is a small peptide between clusterin and Alzheimer’s. approach to identify and determine the cleavage product called amyloid- b (38- crystal structure of polymorphic impu - 42 amino acids, most commonly 40 or DISCOVERING AND rities in samples. 42 amino acids ). Proteinaceous plaques CHARACTERISING POLYMORPHS This approach has been applied to the in the brains of patients suffering from Research in the groups of Bill Jones and determination of the crystal structure of Alzheimer’s disease are comprised of Graeme Day is directed at understand - a new crystal phase of the pharmaceuti - highly ordered fibrillar forms of the ing structure-property relationships in cal compound theophylline, whose pre - amyloid- b peptide. molecular organic solids, applying their viously unknown polymorph was iden - Much recent research has focused on expertise in experimental and computa - tified from analysis of a single crystallite understanding the fibrilisation process tional methods to develop strategies for with a mass of about 3 picograms that of this peptide, and has discovered that characterising and designing materials occurred as a minor component in a a number of disordered smaller, with interesting and useful properties. mixture with a second crystal phase. oligomeric forms of the peptide that Recent highlights from their research The estimated concentration of the vary in size and structure are found groups this year include new methods Below: new polymorph (less than 0.1% by prior to fibril formation and that these for characterising polymorphs, devel - Probing protein weight) is below the limits of detection oligomers have been correlated to the opments in computational methods for aggregation at the of analytical methods routinely used for detrimental effects observed in guiding the synthesis of new materials single molecule level characterisation of organic samples. Alzheimer’s disease. Therefore, it has become of primary importance to characterise these oligomers, which has been a challenge using bulk techniques because of the transient nature and heterogeneity of the oligomeric population. David Klenerman ’s group has turned to single molecule fluorescence tech - niques to resolve and accurately charac - terise these oligomeric populations. In order to do this, researchers in the group have used amyloid- b1-40 monomers, which are each singly labelled with either a red or blue fluo - rescent dye molecule. When red- labelled and blue-labelled amyloid- monomers are combined in equal ratios and allowed to aggregate into oligomers, it becomes possible to dis -

www.ch.cam.ac.uk 11 Science Synthesis: molecules under construction The science of building molecules is at the heart of synthetic libraries for screening using DOS. This has been used to synthesise a library of chemistry at Cambridge. The foundation upon which synthetic macrocyclic peptidomimetics, starting chemistry rests is the fundamental understanding of how and why from simple amino acid building blocks. As well as furthering understanding of molecules react with each other. Studies to further this knowledge biological systems, libraries of complex are critical to inform the design and development of new small molecules created by DOS can provide new drug candidates. A previous chemical methods. Each new method is a new tool, empowering library developed by the group yielded chemists to build the molecules they need. As academic two compounds with activity against discoveries are channelled into practical applications, synthesis multi-drug resistant MRSA strains. meets society’s needs in the most disparate of areas. PICKING THE LOCK The fragment-based approach to drug design involves the screening of small MODEL BEHAVIOUR pharmaceutical companies have built molecules to see how strongly they Although chemists cannot directly up vast libraries of compounds to bind to proteins implicated in disease. It observe molecules reacting with each screen against various diseases for the is heavily influenced by prior knowl - other, technology allows us to simulate discovery of new medicines. New tools edge of the chemical constituents and what we might see if we could. Jonathan for the generation of rationally structure of a receptor protein when Goodman ’s group predicts molecular designed libraries are valuable for designing molecules for screening. structure and reactivity using computer improvement of the screening process. These small molecules are not always modelling, comparing predictions to Two complementary approaches being drug-like compounds, but chemical experimental results to validate the investigated within synthetic chemistry entities that could be incorporated into model. The insight gained can then be are diversity-oriented synthesis (DOS) therapeutics, enabling them to bind to applied to the design of new reactions. and fragment-based screening (FBS). the desired protein. The group recently rationalised the If little is known about the shape or Research within Chris Abell ’s group outcome of the asymmetric Strecker reactivity of a particular receptor, then has used fragment-based screening to reaction, an important method for chemists seeking to target it with a new identify small molecules that could rep - forming amino acids. The reaction drug do not know what kind of mole - resent starting points for the develop - involves forming a new chemical bond cule to start from. DOS is one approach ment of drugs for the treatment of on one side or the other of a flat inter - to solving this problem. A number of Mycrobacterium tuberculosis infection, mediate structure, leading to the pro - different reactions are performed on a or TB. Almost two million people die duction of the amino acid in either of common initial core, which radically each year as a result of TB, highlighting its opposite mirror images. Catalysts can alter its structure. This gives a library of the importance of research into effec - be used to hold the reacting molecules molecules with common medicinal tive therapeutics for its treatment. in a conformation that only allows the chemistry motifs on a number of struc - They identified a small, readily syn - new bond to form on one side of the turally varied cores. Once screening of The equipment in thesised molecule as an effective binder intermediate – making only one mirror such a library returns a ‘hit’, the area of the ITC looks very to the targeted protein. By looking at image configuration of the product. chemical space it occupies can be exam - different from the how the small molecule binds to the A common catalyst for this reaction is ined using traditional medicinal chem - round bottomed protein, they identified the important chiral BINOL-phosphoric acid. Through istry techniques. flasks found in a chemical features for binding. Small computer modelling studies and calcu - David Spring ’s group is working on traditional organic modifications to this first hit were lations, the group established that the the generation of structurally varied synthesis lab made, leading to a more potent binder. relative stability of the key reaction Further screening revealed some intermediate is crucial, a prediction that molecules that also bind strongly to the was confirmed by experiment. This sta - protein, but in a different location. bility can be tuned by synthetic When the protein was treated with both chemists in the design of their interme - molecule A and molecule B, they were diate, and this new insight makes found to bind at the same time but in rational reaction design easier. different regions of the protein. This discovery led the researchers to EXPANDING THE SYNTHETIC incorporate molecules A and B as parts CHEMIST’S TOOLBOX of a larger molecule, joined by a flexible The effect of a medicine is often deter - chemical backbone that allowed both to mined by how a drug molecule physi - bind in their original orientation. These cally interacts with targets such as pro - individual fragment and fragment-link - tein receptors. Both the reactivity and ing strategies enabled direct compari - shape of the molecule are important. son of these two methods for the first In order to find a match between a time. Both methods resulted in similar drug candidate and a target receptor, compounds of comparable potency.

12 www.ch.cam.ac.uk Synthesis

GO WITH THE FLOW great strengths of our department, and Flow chemistry uses mechanisation to also features large in the research carried allow the components of a chemical out in Ian Paterson ’s group. Targets reaction to flow continuously in a include dictyostatin, which has the same stream rather than stirring in a single anticancer mechanism as the drug Taxol, flask. A network of tubes can deliver dif - spirastrellolide A, a potent inhibitor of ferent chemicals at different times, compound. The ability of this opera - protein phosphatase 2A, and two novel meaning that either several reactions can tionally simple process to build previ - Chloptosin, as macrolides isolated from natural sources, take place in a single tube, or that large ously elusive bonds in a single step synthesised by the chivosazole A and reidispongiolide A. amounts of material can be produced. should grant access to novel drug candi - Ley group Efficient and flexible synthetic routes The Innovative Technology Centre dates and functional materials. for the modular construction of these, (ITC) was established by Steven Ley to and other complex polyketide natural apply flow chemistry to traditional syn - CAGING THE BEAST products, are being sought to provide a . By designing and building the In its natural state, white phosphorus sustainable supply for detailed biologi - right machines and computer programs, (P 4) reacts violently with oxygen in the cal evaluation, as well as designing sim - it is possible to add the required chemi - air, a property that makes it a destruc - plified analogues and hybrids that cals to the system, leave the machine to tive weapon. This reactivity can be used retain activity but are simpler to make. run and then collect the desired product productively by chemists, but the mate - Another important feature of the in high purity ready for use. rial is dangerous and difficult to handle. group’s research is the discovery and Recently, researchers in the ITC have Pioneering work in Jonathan development of new synthetic methods. designed systems that can use carbon Nitschke ’s group has demonstrated that More efficient methods of synthesis are dioxide to make important molecules a reusable molecular container can needed that give high levels of stereo - for drug discovery. Expensive infra - make P 4 stable to air and soluble in chemical control in the synthesis of structure is often required to ensure water, apparently indefinitely. It is biologically important natural products. that gases can be stored and used safely thought that reaction with oxygen is without risk of leakage or explosion. prevented by the restrictive size of the DYNAMIC MATERIALS Gas-permeable tubing has enabled cage, which is constructed in a self- Oren Scherman ’s group has developed scientists from the ITC to deliver carbon assembly process from four iron atoms a ‘smart’ polymeric material – a hydro - dioxide gas safely, as a cheap and read - and six organic linkers. gel with controllable viscosity. Trad- ily available reagent to form carboxylic P4 can be ejected from the cage by the itionally, polymer properties can be acids in very high purity and yield. The addition of a replacement molecule – in altered by cross-linking – the formation reaction works on multigram scales, this case, benzene – and then reacted as of chemical bonds between individual which is highly encouraging for appli - required. In addition to aiding the lab polymer chains. These processes are cation in industry where kilogram manipulation of P 4, this technology generally irreversible, and so the mate - quantities of chemical compounds are could also be applied to the clean-up of rials are very difficult to reuse or recy - required to manufacture medicines. phosphorus spills. The group is now cle. A current area of research is the Following the safe and successful use investigating larger molecular containers development of reversibly cross-linked of carbon dioxide, ITC researchers are in the hope of encapsulating more com - polymers, the properties of which can now developing the system to incorpo - plex guest molecules. be controlled by external stimuli such rate other useful reactive gases for the as heat, light, pH or electrical current. synthesis of important molecules. MAKING NATURE’S MOLECULES The group designed and synthesised Some of the most influential drugs of two polymers with complementary EXPEDIENT METHODS the past century have not been discov - linker groups, and combined them with FOR ELUSIVE BONDS ered in a laboratory, but in the natural a barrel-shaped molecular container in Research in Matthew Gaunt ’s group world. While nature provides these water, forming an aqueous gel. The con - focuses on C–H activation – the strategy potent molecules, isolation from their tainer molecules hold the linker groups of making new chemical bonds by natural sources can be inefficient, together and enable a network of cross- direct reaction with a comparatively impractical and hugely damaging to the links to form, greatly increasing the vis - inert carbon–hydrogen bond, rather environment, as they often only contain cosity of the gel. No discrete chemical than a less common but more reactive tiny amounts of the molecules. bonds are formed, so the change is bond to a non-hydrogen atom (C–X). Steven Ley ’s group has recently reversible and can be controlled by Although C–X bonds may be easier to achieved the synthesis of chloptosin, a heating, cooling, and addition of more react with, and easier to differentiate naturally occurring molecule with container molecules. from other bonds for a selective reaction, potential activity against pancreatic can - Materials of this type have many they often serve no other purpose and so cer. The development of new chemistry potential applications, including the must be installed prior to the reaction or was pivotal to the design of the syn - simple but significant concept of slow- removed afterwards. C–H activation is at thetic route, with a new method to release drug delivery – instead of pills the cutting edge of synthetic chemistry make the piperazic acid components to be taken daily, an entire course of and seeks to eliminate these inefficient present in the structure of chloptosin, treatment could be administered in a ‘pre-functionalisation’ steps, as well as which are important structural features single injection of the medicine dis - providing new tools to complement of many other bioactive molecules. persed in a viscous hydrogel. existing methods and access challenging This new methodology was imple - chemical architectures. mented successfully and, overcoming a Cambridge has a proud tradition of The group’s recent development of a number of synthetic challenges along meta-selective arylation reaction, which the way, they assembled chloptosin in research in synthetic chemistry. Its links aromatic building blocks together, an efficient and elegant fashion. The strength and depth is illustrated in the fulfils both of these criteria. It operates synthesis offers the opportunity to on aromatic C–H bonds, and of the make significant quantities of the natu - understanding, discovery and application three possible sites of bond formation, ral product, allowing the promising of new chemistry – addressing society’s the reaction cleanly selects the meta- bioactivity of both chloptosin and its needs from the design of new functional position – the most difficult to access by analogues to be assessed. conventional chemistry in this class of Natural product synthesis is one of the materials to the treatment of disease.

www.ch.cam.ac.uk 13 Chat lines Property prediction and modelling reactions

associated with a wide range of inflam - The Theory, Modelling and Informatics RIG focuses on the matory diseases in the mammalian development and application of theoretical and computational immune system, recognise and become activated by pathogenic molecules. chemistry techniques. The overall aims are to deepen our The group is simulating systems of understanding of the properties of classical, quantum and receptor complexes – in some cases approaching a million atoms in size – molecular systems, to model and interpret experimental data, and and probing the thermodynamic con - to design new algorithms and tools for modelling, simulation and tributions by individual components of the complex. This molecular-level infor - data manipulation. Topics are broad in range, from the prediction mation is being combined with in vivo of properties of small molecules to large biomolecular systems assays to identify the determinants of such as protein-ligand complexes, and from modelling chemical selectivity, towards the design of drugs or vaccines. reactions to mesoscopic systems and the atmosphere. By its nature, the group is highly interdisciplinary and collaborative, CAUSE AND EFFECT Even when furnished with structural and projects span academic as well as industrial research partners. information on the interactions of mole - cules with targets, do we really under - stand how drugs work? When a drug is MOLECULAR DESIGN antagonist, exhibiting the highest affinity taken, it will – or will not – be dissolved Robert Glen ’s group uses molecular of any novel compound for this receptor and absorbed in the stomach and diges - informatics approaches to predict prop - to date. The group is now synthesising tive tract, become distributed into target erties of molecules in chemistry and and testing further agonist, partial ago - organs (as well as those responsible for chemical biology. In the context of drug nist, and antagonist molecules. causing side-effects) and, finally, be discovery, significant progress has been metabolised by enzymes and excreted. made in the design of new active mole - TAKING A TOLL Given the complexity of even a single cules targeted to G-protein-coupled Not all drug binding events fit the sim - human being – let alone variation receptors (GPCRs). ple one ligand, one target case. As our between people – it is, in reality, still very One such GPCR is activated by apelin knowledge of the biochemical interac - difficult to predict how a new drug peptide hormones, and is a putative tar - tome expands, it is becoming clear that Below, molecular works, or its potential side-effects. get for treatment of cardiovascular and many biological processes and chemical switches: trans - However, in recent years large data - metabolic diseases. Experimental data reactions within a cell are propagated membrane GPCRs, bases such as ChEMBL have been pub - have suggested that a conserved, sec - by heterogeneous assemblies of macro - represented here lished, so we can now use data mining ondary structural feature called a b-turn molecules, hampering traditional drug by a model of the algorithms from the computer science may exist in apelin and is likely to be design approaches. apelin receptor, domain for the analysis of chemical and critical for recognition. In the absence The group of Peter Bond is utilising are important biological information to explain the of high-resolution information for the molecular modelling and simulation signalling proteins bioactivity profile of a potential drug. interaction of apelin with its receptor, approaches to understand how such that transduce a Andreas Bender ’s group is currently the group has used a combined in silico assemblies function in signalling cas - wide range of devising new ways to integrate chemi - and in vitro approach to unravel the cades, and how they may be targeted signals into cellular cal and biological data relevant to these structure-activity relationships of apelin therapeutically. Recently, progress has responses, and are types of questions, using principles of receptor ligands. been made in unravelling the mecha - hence major chemoinformatics to create statistical simulations, in nisms by which toll-like receptors, therapeutic targets models around chemical fingerprints which Newton’s equations of motion for the design of novel compounds are used to propagate a molecular sys - with increased potency or a more tem via an empirically derived energy favourable side effect profile. In turn, function, were used to study the sol - this work can also be used for a more vated conformations of a series of cyclic comprehensive safety assessment of apelin peptides. Subsequent experimen - drugs – work which is part of currently tal screening showed the apelin receptor ongoing studies within the group. recognises only those peptides pre - dicted by simulation to contain b-turns. ASSEMBLING THE PIECES Following this work, novel, bivalent The groups of Daan Frenkel , David ligands were designed, in which two Wales and Mark Miller are working cyclic b-turn moieties are proposed to together to understand the spontaneous act as anchors, separated by a linker self-assembly of complex structures motif that may act as a receptor switch. from simple building blocks. Self- One of the ligands was shown experi - assembling molecular systems are of mentally to be a competitive apelin great interest in nanotechnology,

14 www.ch.cam.ac.uk Theoretical

nanomedicine, colloidal science, and understand the mechanisms of folding crystal formation processes. of complete proteins, while many bio - Right, pathways to They are also used by nature in bio - molecular conformational changes also crystallisation: the molecular recognition, protein folding often involve folding transitions. energy landscape and macromolecular complex forma - However, the results of such simula - for low-energy tion. When biological self-assembly tions are highly dependent upon the crystalline clusters turns against its host, diseases such as accuracy of the underlying force field. is illustrated via a Alzheimer’s can result. Unfortunately, With this in mind, the group has disconnectivity such processes take place on scales diffi - undertaken the refinement of existing graph. Four cult to access by experimental methods. force fields by matching the properties truncated lines The groups therefore use simulations of simple peptides measured in simula - corresponding to and energy landscape exploration algo - tions and experiment. This effort energetic minima rithms to understand the design princi - yielded a highly optimised force field reveal a mixture of ples of self-assembly and aggregation. with an accurate balance of protein face centred cubic A major difficulty in understanding conformations, enabling the group to (FCC) and self-assembly processes is the large simulate the complete, ab initio folding hexagonal close phase space, or dimensionality, of the of a variety of small proteins to their packed (HCP) system – there are often likely to be native structures. structures many possible arrangements separated by multiple barriers, making it difficult THE RIGHT REACTION to explore the underlying energy land - When modelling molecular processes, calculations for the fact that electrons scape that defines the mechanisms and accuracy is key, but at what cost? There ‘move’ in a correlated fashion with pathways towards assembly. Therefore, is always a trade-off between the preci - respect to each other. This is a crucial it makes sense to simplify the models sion of the method and the time feature of any accurate description of used, in order to speed up calculations required to complete a calculation. A chemical bonds. and unearth fundamental rules. very accurate method might require An electronic correlation is, in fact, a One approach has been to restrict the more computer resource than is avail - quantum manifestation of ‘entangle - problem to two dimensions and, in par - able within the time required for an ment’ of combinatorially many differ - ticular, to uncover the basic design answer to be found. ent electronic configurations, called principles of self-assembly on curved Jonathan Goodman ’s group carries Slater determinants. Ali’s group has surfaces. Computational algorithms are out computational calculations to been developing a novel Monte Carlo being used to explore the energy land - understand reaction mechanisms, par - method in which a vast number of elec - scape of assembling particles and ticularly in organocatalysis, and recently tronic configurations, called Slater extended objects on curved surfaces, studied the reliability of the many com - determinants, are sampled, using popu - with a particular focus on the emer - putational methods that are available to Below, linking lation dynamics of walkers which gence of defect patterns that are known study molecular processes. drugs, targets, and inhabit Slater determinant space. to occur experimentally. The group’s detailed survey of a wide mechanisms of The method has allowed accurate The exploration of such processes will range of reactions in organic chemistry action: A particular quantum mechanical calculations of help to understand commonly observed looked at the reliability of different bioactivity profile electronic correlation to be performed assemblies in nature, and will guide methods based on density functional for compounds on quite sizeable molecules – up to 60 template self-assembly of new materials theory (DFT), a quantum mechanical against a series of electrons, Slater determinant spaces of with desirable technological properties. approach to electronic structure calcula - proteins may be more than 10 100 determinants. Because Another area of interest is crystal tion, for transition state calculations, used to predict of the sheer volume of calculations, such nucleation. Nucleation and growth are which are the key requirement for phenotypic systems have previously thought to be fundamental to many organic and inor - analysing molecular processes. observations. In tractable only with quantum computers, ganic processes, and it would be desirable From this extensive study, recom - this case, the which have yet to be built! The new algo - to control and optimise the early stages of mendations could be made regarding a observation of side rithm developed in the group, therefore, crystallisation that ultimately determine selection of methods that gave particu - effects is provides a significant boost for classical the structure and properties of novel syn - larly good value in terms of the ratio of explained; activity computation, in other words, computing thetic or biocomposite materials. its precision to its computational cost, on the µ-opioid with ordinary machines. Typically, crystal nucleation is rare – while also giving good absolute preci - receptor can be for the process to occur, a high free sion in its results. linked to energy barrier must be crossed, making addiction, and Advances in the RIG direct observation of freezing events dif - MOVING CALCULATIONS activity on have significant impact ficult in conventional simulations. Ali Alavi ’s group is interested in the cyclooxygenase-1 Algorithms based on geometry optimi - electronic correlation problem: that is, can be linked to in areas ranging from sation techniques are being used to how to account in electronic structure intestinal bleeding the identification of safe identify pathways and transition states along the energy landscape, and hence therapeutic small provide structural and mechanistic molecules, the insights into the crystallisation process. development of new FROM SEQUENCE TO STRUCTURE approaches to exploit Robert Best ’s group is interested in simulating the dynamics of biomole - experimental data, cules, particularly in the context of pro - and the design of tein folding and assembly. Protein fold - self-assembling ing is an important field in biomedical research as a range of debilitating dis - nanostructures, catalysts, eases result from protein misfolding. sensors, and crystals. Simulation approaches can help to

www.ch.cam.ac.uk 15 Outreach Enthusing future chemists

Outreach is an important part of the department’s to 18. It aims to raise aspirations and mission. From the annual open day to hosting visits encourage students to focus on their higher education choices. from students and teachers, the aim is to encourage Teachers have an opportunity to young people to study chemistry, and promote an access the facilities of the department with the free residential courses offered interest in science among the wider public. as part of The Goldsmiths’ Company Science for Society Courses. Science teachers attend lectures aimed at broad - ening their perspective on subjects allied to the A-level syllabus. The department is also involved in the International Chemistry Olympiad, and helps set the questions and select the team in association with the Royal Society of Chemistry. Once selected, the team spends a week in the department preparing for the competition. In 2009, the University of Cambridge acted as joint host of the Hundreds of 41st International Chemistry Olympiad, children and their providing the infrastructure for 260 parents visit the students from 69 countries to under - department every take a practical and theory exam. March for our Accompanied by teacher mentors, the open day, with occasion showcased the facilities of the Peter Wothers’ department and the university. lecture packing the theatre, and CHEMISTRY OPEN DAY students helping The open day run by the department as the kids with fun part of the University Science Festival experiments offers an ideal opportunity for under - The department has a rich and varied the opportunity for 80 year 7 and 8 stu - graduates and PhD students to engage outreach programme interacting with dents to spend a day in a university with members of the public. Although children as young as five to secondary department where they take part in the emphasis is necessarily on ‘fun’ school teachers. One of the most practical chemistry. The Salters’ chemistry, schools also make full use of important areas of outreach is forging Chemistry Camp is a two-day residen - the day to allow pupils to get involved links with school pupils to maintain tial course aimed at year 10 pupils giv - in a way which is often not available in their interest in science. The department ing them an opportunity to explore the class. Peter Wothers’ lecture has a strong acts as a host for a number of summer fun of chemistry and develop a long- educational basis, and is given to 1000 schools organised by external organisa - term interest in the subject and its local school children, in addition to the tions who can make full use of teaching applications in modern life. public lectures on the day. staff, technicians and lab facilities. The department is enthusiastic when Salters’ Festival of Science provides SUMMER SCHOOLS approached by external organisations – An important part of departmental out - engaging the interest of the wider com - reach is participation in the Sutton Trust munity in science is an essential part of summer schools. These free residential providing for the future. courses are specifically designed for year 12 students from state-maintained schools, and priority is given to those who come from schools with a low overall A-level point score, and who would be the first generation in their family to attend university. The school is an ideal opportunity to discover what it is like to live and study as a first-year undergraduate student of Cambridge and encourage the students to consider taking a degree at the University of Cambridge. Teaching staff also participate in a similar scheme run by the educational charity Teach First – called Higher Education Access Programme for Schools (HEAPS) for teenagers aged 16

16 www.ch.cam.ac.uk For more information about the department’s people and science, please visit our website at www.ch.cam.ac.uk DDeeppaarrttmmeenntt ooff CChheemmiissttrryy UUnniivveerrssiittyy ooff CCaammbbrriiddggee LLeennssffiieelldd RRooaadd CambridgCea CmBb2ri d1EgWe www.ch.cCaBm2.a 1cE.uWk www.ch.cam.ac.uk