DOCSLIB.ORG

Biophysical Approaches for the Study of Interactions Between Molecular Chaperones Cite This: Chem

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biophysical Approaches for the Study of Interactions Between Molecular Chaperones Cite This: Chem ChemComm View Article Online FEATURE ARTICLE View Journal | View Issue Biophysical approaches for the study of interactions between molecular chaperones Cite this: Chem. Commun., 2015, 51, 14425 and protein aggregates Maya A. Wright, Francesco A. Aprile, Paolo Arosio, Michele Vendruscolo, Christopher M. Dobson and Tuomas P. J. Knowles* Molecular chaperones are key components of the arsenal of cellular defence mechanisms active against protein aggregation. In addition to their established role in assisting protein folding, increasing evidence indicates that molecular chaperones are able to protect against a range of potentially damaging aspects of protein behaviour, including misfolding and aggregation events that can result in the generation of aberrant protein assemblies whose formation is implicated in the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The interactions between molecular chaperones and different amyloidogenic protein species are difficult to study owing to the inherent heterogeneity of Creative Commons Attribution 3.0 Unported Licence. the aggregation process as well as the dynamic nature of molecular chaperones under physiological conditions. As a consequence, understanding the detailed microscopic mechanisms underlying the nature and means of inhibition of aggregate formation remains challenging yet is a key objective for protein Received 3rd May 2015, biophysics. In this review, we discuss recent results from biophysical studies on the interactions between Accepted 7th August 2015 molecular chaperones and protein aggregates. In particular, we focus on the insights gained from current DOI: 10.1039/c5cc03689e experimental techniques into the dynamics of the oligomerisation process of molecular chaperones, and highlight the opportunities that future biophysical approaches have in advancing our understanding of the www.rsc.org/chemcomm great variety of biological functions of this important class of proteins. This article is licensed under a 1 Protein folding and aggregation Open Access Article. Published on 10 8 2015. Downloaded 2021-10-01 11:01:23. Proteins take part in virtually all of the key molecular processes Department of Chemistry, University of Cambridge, Lensfield Road, in living organisms by interacting with a wide range of bio- Cambridge CB2 1EW, UK. E-mail: [email protected]; Tel: +44 (0)1223 336300 molecules, including other proteins. In order to function properly, Maya Wright received her Bachelor Francesco A. Aprile received his of Science in Chemistry from PhD degree in Biology at the Imperial College London in June University of Milano-Bicocca 2013. The following year she (Italy), having worked on the received a Master’s degree in molecular characterization of biophysical chemistry from the protein homeostasis and self- University of Cambridge under the assembly processes. Currently, supervision of Professor Tuomas he is a post-doctoral researcher Knowles, and has since stayed on at the Department of Chemistry, to pursue a PhD. Her interests focus University of Cambridge (UK), on the development of microfluidic where he is devising novel techniques for the characterisation classes of protein therapeutics by Maya A. Wright of the dynamics of molecular Francesco A. Aprile rationally manipulating the chaperone systems. target-recognition of antibodies, molecular chaperones, and other proteins of therapeutic interest. This journal is © The Royal Society of Chemistry 2015 Chem. Commun., 2015, 51, 14425--14434 | 14425 View Article Online Feature Article ChemComm proteins generally have to fold into specific three-dimensional misfolding through inappropriate intramolecular interactions structures known as native states. The folding of proteins into between hydrophobic amino acid residues on nascent chains, and these conformations is, at least at low concentrations, a spon- between nascent chains and other proteins or biomolecules taneous self-assembly process in which their free energy is within the cytoplasm.7,8 In order to counteract protein misfolding, minimised,1 through the optimization of intramolecular inter- cells contain a range of protective mechanisms, notably molecular actions within the protein chain as well as protein–solvent chaperones, which assist proteins in attaining their native interactions.1–3 In particular, it is generally favourable for conformations. However, some proteins escape these control amino acid residues with hydrophobic side chains to be buried mechanisms and form partially folded or misfolded states within the folded native structure, shielded from the aqueous which lack their intended biological function and which are cell medium.3 However, at higher concentrations, such as those particularly prone to aggregation.7 found in the cellular environment, the native state can become Protein aggregates can range from amorphous species to metastable relative to self-assembly into aggregates.4–6 In addi- highly ordered b-sheet rich amyloid fibrils. Amorphous aggre- tion, incompletely formed nascent protein chains emerging gates are largely disordered deposits and can be degraded readily from the ribosome are typically exposed to the highly crowded within the cell,9,10 whereas amyloid aggregates are highly persis- cellular environment in an unfolded state for long periods with tent and stable assemblies of proteins. The formation of such respect to the time required for their folding.7 Indeed, slow aggregates is associated with the onset and development of a rates of codon translation significantly increase the chance of range of disorders such as Alzheimer’s and Parkinson’s diseases, Paolo Arosio obtained his master’s Michele Vendruscolo obtained a degree in chemical engineering PhD in condensed matter physics from the Politecnico di Milano in at SISSA (Trieste, Italy) in 1996. Creative Commons Attribution 3.0 Unported Licence. 2007, and his PhD from the Swiss Since 2001 he works at the Federal Institute of Technology Department of Chemistry, Univer- ETH Zurich in 2011. Since 2012 sity of Cambridge (UK), where his he is a post-doctoral researcher at research is primarily focused on the Department of Chemistry at the investigation of the molecular the University of Cambridge, UK, origins of misfolding diseases. whereheiscurrentlytherecipient of a Marie Curie fellowship. His This article is licensed under a research interests, at the interfaces Paolo Arosio between engineering, biophysics Michele Vendruscolo and physical chemistry, focus on Open Access Article. Published on 10 8 2015. Downloaded 2021-10-01 11:01:23. biomolecular reactions, in particular understanding and controlling the protein assembly and protein interaction processes that underlie problems of key fundamental and practical importance in biology and biotechnology. Chris Dobson was an under- Tuomas Knowles studied Biology graduate and graduate student at the University of Geneva and at Oxford University, and then Physics at ETH Zurich from became an Assistant Professor where he graduated in 2004. He at Harvard University before obtained a PhD in Biological returning to Oxford where he Physics from the University of was a Professor of Chemistry. Cambridge in 2008 and joined He is now the John Humphrey the faculty at the Department Plummer Professor of Chemical of Chemistry at Cambridge in and Structural Biology at 2010 where he is presently Cambridge University and professor of Physical Chemistry Master of St John’s College. His and Biophysics. His work is Christopher M. Dobson research interests are directed Tuomas P. J. Knowles focused on the development and primarily at understanding the application of experimental and mechanisms of protein folding and misfolding and the links theoretical methods based on the physical sciences to study between these processes and human disease. biomolecular behaviour and interactions. 14426 | Chem. Commun., 2015, 51, 14425--14434 This journal is © The Royal Society of Chemistry 2015 View Article Online ChemComm Feature Article type II diabetes, and the formation of eye lens cataracts.11–14 in the previous section. However, increasing evidence indicates The mechanism by which soluble monomeric proteins assem- that assisting nascent protein chains in reaching their native ble into fibrils involves several distinct microscopic processes.15 conformations is just one of the many functions of molecular Typically, protein monomers first assemble into soluble low chaperones (Fig. 1A). Indeed, several studies have shown that molecular weight oligomers through primary nucleation. These molecular chaperones also play a more direct role in protecting oligomers then elongate via monomer addition, leading to the against protein aggregation by refolding non native proteins and formation of long and highly organised mature fibrils. Amyloid promoting disaggregation of misassembled proteins (Fig. 1B formation is accelerated by fragmentation of existing fibrils and and C), as well as inhibiting fibril formation by establishing inter- other forms of secondary events, for example secondary nuclea- actions with a variety of amyloidogenic species such as partially tion in which the surfaces of mature fibrils catalyse the nuclea- folded intermediates, toxic oligomers, and mature amyloid fibrils tion of monomers as a feedback system that results in the (Fig. 1D and E).24–34 For example, the extracellular molecular 15,16 production of new aggregates. To counteract the numerous chaperones a2-macroglobulin and clusterin have been shown to pathways
Load more

Recommended publications
  • Towards Complete Descriptions of the Free Energy Landscapes of Proteins
    Sequence-Based Predictions of Protein Solubility Michele Vendruscolo Department of Chemistry University of Cambridge Protein folding The fundamental code for protein folding is provided by the amino acid sequence. Amino acid sequences encode the whole free energy landscape of proteins Not only the native structure but also all the other states and the corresponding pathways of interconversion are encoded in the amino acid sequence of a protein. Does the amino acid sequence encode also for aggregation? Physico-chemical principles of protein aggregation Hydrophobicity, charge and secondary structure propensity are correlated with the changes in the aggregation rates upon mutation. Chiti et al. Nature 2003 Sequence-based prediction of aggregation rates The combination of sequence-dependent factors and environmental factors enables the prediction of aggregation rates over a broad range of timescales (from seconds to weeks) 0 ln(k) = åakIk + åak Ek -1 -2 ) k ( ln(k): logarithm of the aggregation rate k g o l -3 d e hydr t I : hydrophobicity a l -4 pat u c I : hydrophobic patterns l a C I : -helical propensity -5 I : -sheet propensity ch I : charge contribution -6 EpH: pH of the solution -7 -7 -6 -5 -4 -3 -2 -1 0 Eionic: ionic strength Experimental log(k ) Econc: polypeptide concentration DuBay et al. J. Mol. Biol. 2004 Prediction of aggregation-prone regions of -synuclein The aggregation propensity is a function of the physico-chemical properties of the amino acid sequence (hydrophobicity, charge, etc). We have developed the Zyggregator method to predict aggregation rates and aggregation-prone regions (www-vendruscolo.ch.cam.ac.uk) Tartaglia et al.
    [Show full text]
  • Towards Complete Descriptions of the Free-Energy Landscapes of Proteins by Michele Vendruscolo and Christopher M
    FirstCite® Phil. Trans. R. Soc. A (2005) e-publishing doi:10.1098/rsta.2004.1501 Towards complete descriptions of the free-energy landscapes of proteins By Michele Vendruscolo and Christopher M. Dobson Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK ([email protected]) In recent years increasingly detailed information about the structures and dynamics of protein molecules has been obtained by innovative applications of experimental techniques, in particular nuclear magnetic resonance spectroscopy and protein engi- neering, and theoretical methods, notably molecular dynamics simulations. In this article we discuss how such approaches can be combined by incorporating a wide range of different types of experimental data as restraints in computer simulations to provide unprecedented detail about the ensembles of structures that describe pro- teins in a wide variety of states from the native structure to highly unfolded species. Knowledge of these ensembles is beginning to enable the complete free-energy land- scapes of individual proteins to be defined at atomic resolution. This strategy has provided new insights into the mechanism by which proteins are able to fold into their native states, or by which they fail to do so and give rise to harmful aggregates that are associated with a wide range of debilitating human diseases. Keywords: protein folding; energy landscape; protein misfolding; protein aggregation; amyloid diseases; computer simulations 1. Introduction Characterizing the nature of partially folded states of proteins is crucial for under- standing the determinants of many aspects of their behaviour, including the stability of the native state, the kinetics of folding and the mechanisms of misfolding (Ven- druscolo et al.
    [Show full text]
  • Paul Robustelli, Ph.D. Assistant Professor of Chemistry [email protected] Dartmouth College Profes
    Paul Robustelli, Ph.D. Assistant Professor of Chemistry [email protected] Dartmouth College Professional Experience § Dartmouth College (Jan 2020–Present) § Assistant Professor of Chemistry § Member, Neukom Faculty Cluster of Computational Science § Member, Department of Biochemistry and Cell Biology § D.E. Shaw Research (2013-2019) Scientist § Developing Improved Physical Models for the Accurate Simulation of both Folded and Disordered Protein States § Elucidating Dynamic Binding Modes of Small Molecules with Intrinsically Disordered Proteins and Rationally Designing Tighter Binders § Columbia University Medical Center (2011-2013) NSF Postdoctoral Research Fellow § Mentor: Arthur G. Palmer III § Studying the Role of Conformational Dynamics in Protein Function with NMR Spectroscopy and Molecular Simulations § University of Cambridge, Department of Chemistry (2006-2011) Graduate Research Assistant § Mentor: Michele Vendruscolo § Development and Application of Novel Computational Methods for Protein Structure Determination from NMR Chemical Shifts § Pomona College, Department of Chemistry (2004-2006) Undergraduate Research Assistant § Mentor: Wayne E. Steinmetz § Determination of the Structure and Conformational Dynamics of Tricothecene Mycotoxins with NMR Spectroscopy and Molecular Modeling Education § University of Cambridge - Ph.D. in Chemistry (2010) § Dissertation Title: Protein Structure Determination from NMR Chemical Shifts § Supervisor: Michele Vendruscolo § Pomona College - B.A. in Chemistry with Minor in Mathematics
    [Show full text]
  • A Statistical Mechanical Method to Optimize Energy Functions for Protein Folding
    A statistical mechanical method to optimize energy functions for protein folding Ugo Bastolla*†, Michele Vendruscolo‡, and Ernst-Walter Knapp*† *Freie Universita¨t Berlin, Department of Biology, Chemistry and Pharmacy, Takustrasse 6, D-14195 Berlin, Germany; and ‡Oxford Centre for Molecular Sciences, New Chemistry Laboratory, Oxford OX1 3QT, United Kingdom Communicated by Vitalii Goldanskii, Russian Academy of Sciences, Moscow, Russia, December 22, 1999 (received for review May 12, 1999) We present a method for deriving energy functions for protein A second class of methods (19–23) aims at providing the folding by maximizing the thermodynamic average of the overlap largest possible thermodynamic stability to the target proteins. with the native state. The method has been tested by using the These methods optimize quantities related to the Z score (24), pairwise contact approximation of the energy function and gen- measuring the difference between the energy of the native state erating alternative structures by threading sequences over a da- and the average energy of the alternative states in units of the tabase of 1,169 structures. With the derived energy function, most standard deviation of the energy. Goldstein et al. (19, 20), native structures: (i) have minimal energy and (ii) are thermody- inspired by a spin-glass analysis, derived efficient parameters for namically rather stable, and (iii) the corresponding energy land- fold recognition. More recently, the method was extended to scapes are smooth. Precisely, 92% of the 1,013 x-ray structures are protein structure prediction via simulated annealing (21). Hao stabilized. Most failures can be attributed to the neglect of inter- and Scheraga applied a similar method to the more difficult actions between chains forming polychain proteins and of inter- problem of deriving an energy function for folding simulations actions with cofactors.
    [Show full text]
  • Assistant Professor in Experimental Biological Physics
    THE BIOLOGICAL PHYSICIST The Newsletter of the Division of Biological Physics of the American Physical Society Vol 7 N o 5 Dec 2007 DIVISION OF BIOLOGICAL PHYSICS EXECUTIVE COMMITTEE Chair In this Issue Dean Astumian [email protected] Immediate Past Chair NEWS FEATURE Marilyn Gunner [email protected] APS Statement on Climate Change.…………..…...…..….....2 Chair-Elect PRL HIGHLIGHTS………………………………………..…..….....4 James Glazier [email protected] PRE HIGHLIGHTS……………………..……………...…..…..……9 Vice-Chair SPECIAL DBP ANNOUNCEMENT: Stephen Quake [email protected] 2008 Delbrück Prize...………………………………..….........13 Secretary/Treasurer SPECIAL DBP ANNOUNCEMENT: Shirley Chan DBP Welcomes New APS Fellows…….……………...........14 [email protected] APS Councilor SPECIAL DBP ANNOUNCEMENT: Robert Eisenberg Student Travel Grants for 2008 APS March Meeting........15 [email protected] SPECIAL DBP ANNOUNCEMENT: Members-at-Large: Workshop on Opportunities in Biological Physics………16 Stephen J. Hagen [email protected] JOB ADS…………………………………………………………20 Chao Tang [email protected] HFSP CALL FOR LETTERS OF INTENT………...……………...........25 Réka Albert [email protected] Brian Salzberg [email protected] John Milton [email protected] This issue of THE BIOLOGICAL PHYSICIST Jin Wang brings you a special news feature on the recent APS [email protected] statement on climate change. We bring you the ------------------------------------------ announcement of the 2008 Max Delbrück Prize in Biological Physics, and welcome new APS fellows who have made significant contributions to biological Newsletter Editor physics, as well as job ads and a call for letters of Sonya Bahar [email protected] intent from the Human Frontier Science Program. Website Manager Enjoy! Andrea Markelz – SB [email protected] 1 NEWS FEATURE APS STATEMENT ON CLIMATE CHANGE S.
    [Show full text]
  • Department of Chemistry University of Cambridge Biennial Report 2012 Edited and Designed by Sarah Houlton Photographs: Nathan Pitt and Caroline Hancox
    Chemistry @ Cambridge Department of Chemistry University of Cambridge 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 Jane Clarke 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. David Klenerman 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.
    [Show full text]
  • Protein Solubility and Protein Homeostasis: a Generic View of Protein Misfolding Disorders
    Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders Michele Vendruscolo, Tuomas P.J. Knowles, and Christopher M. Dobson Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom Correspondence: [email protected] According to the “generic view” of protein aggregation, the ability to self-assemble into stable and highly organized structures such as amyloid fibrils is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but rather a property shared by most proteins. At the same time, through a wide variety of techniques, many of which were originally devised for applications in other disciplines, it has also been established that the maintenance of proteins in a soluble state is a fundamental aspect of protein homeostasis. Taken together, these advances offer a unified framework for understanding the molecular basis of protein aggregation and for the rational development of therapeutic strategies based on the biological and chemical regulation of protein solubility. irtually every complex biochemical process structures that results from protein folding, and Vtaking place in living cells depends on the which serve to bring key functional groups into ability of the molecules involved to self- close proximity, has enabled living systems to assemble into functional structures (Dobson develop an astonishing diversity and selectivity 2003; Robinson et al. 2007; Russel et al. 2009), in their underlying chemical processes by using and a sophisticated quality control system is a common set of just 20 basic molecular com- responsible for regulating the reactions leading ponents, the amino acids (Dobson 2003).
    [Show full text]
  • Ai Fini Di Pubblicazione
    Daniele Granata Ai fini di pubblicazione B [email protected] Personal information Date of birth 18 April 1984 Place of birth Roma Nationality Italian Institution Temple University, Philadelphia, USA Phone number +1-215-410-0348 (mobile), +1-215-204-4221 (office) Email [email protected] , [email protected] Scientific and research interest Computational Biophysics. Protein physics. Folding and structure prediction from experimental data. Molecular Dynamics simulation and enhanced sampling techniques. Knowledge-based potentials for native state discrimination and protein-protein interactions. Intrinsically disordered proteins. Ion channels. Sta- tistical mechanics. Bioinformatics and methods development. Education 2014–Present Postdoctoral Researcher, Temple University, Philadelphia, USA. Department Institute for Computational Molecular Science, M.L. Klein’s group Topic Ion channels and application of statistical mechanics to bioinformatics and data analysis Supervisor Prof. M.L. Klein, Dr. V. Carnevale 2009–2013 Ph.D. Degree cum laude in Physics and Chemistry of Biological Systems, SISSA - International School for Advanced Studies, Trieste, Italy. Thesis Characterizing structure and free energy landscape of proteins by NMR-guided metadynamics Supervisor Prof. A. Laio, Prof. M. Vendruscolo Description A new enhanced sampling technique in Molecular Dynamics to study efficientely the structure and folding of globular and intrinsicaly disordered proteins exploiting experimental NMR data 2006–2009 Master’s Degree (Laurea Specialistica) cum laude in Physics, Università di Roma “La Sapienza”, Roma, Italy. Thesis Optimal states of human red blood cells metabolism. Supervisors Prof. A. Giansanti, Dr. A. De Martino Description Study of the fluxes, stability and responses to enzymopathies for red blood cell metabolic network, based on Von Neumann’s growth model 2003–2006 Bachelor’s Degree (Laurea Triennale) cum laude in Physics, Università di Roma “La Sapienza”, Roma, Italy.
    [Show full text]
  • Biophysical Approaches for the Study of Interactions Between Molecular Chaperones Cite This: Chem
    ChemComm View Article Online FEATURE ARTICLE View Journal | View Issue Biophysical approaches for the study of interactions between molecular chaperones Cite this: Chem. Commun., 2015, 51, 14425 and protein aggregates Maya A. Wright, Francesco A. Aprile, Paolo Arosio, Michele Vendruscolo, Christopher M. Dobson and Tuomas P. J. Knowles* Molecular chaperones are key components of the arsenal of cellular defence mechanisms active against protein aggregation. In addition to their established role in assisting protein folding, increasing evidence indicates that molecular chaperones are able to protect against a range of potentially damaging aspects of protein behaviour, including misfolding and aggregation events that can result in the generation of aberrant protein assemblies whose formation is implicated in the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The interactions between molecular chaperones and different amyloidogenic protein species are difficult to study owing to the inherent heterogeneity of the aggregation process as well as the dynamic nature of molecular chaperones under physiological conditions. As a consequence, understanding the detailed microscopic mechanisms underlying the nature and means of inhibition of aggregate formation remains challenging yet is a key objective for protein Received 3rd May 2015, biophysics. In this review, we discuss recent results from biophysical studies on the interactions between Accepted 7th August 2015 molecular chaperones and protein aggregates. In particular, we focus on the insights gained from current DOI: 10.1039/c5cc03689e experimental techniques into the dynamics of the oligomerisation process of molecular chaperones, and highlight the opportunities that future biophysical approaches have in advancing our understanding of the www.rsc.org/chemcomm great variety of biological functions of this important class of proteins.
    [Show full text]
  • Third Generation Antibody Discovery Methods: in Silico Rational Design Cite This: Chem
    Chem Soc Rev View Article Online REVIEW ARTICLE View Journal | View Issue Third generation antibody discovery methods: in silico rational design Cite this: Chem. Soc. Rev., 2018, 47,9137 Pietro Sormanni, * Francesco A. Aprile and Michele Vendruscolo * Owing to their outstanding performances in molecular recognition, antibodies are extensively used in research and applications in molecular biology, biotechnology and medicine. Recent advances in experimental and computational methods are making it possible to complement well-established in vivo Received 25th June 2018 (first generation) and in vitro (second generation) methods of antibody discovery with novel in silico DOI: 10.1039/c8cs00523k (third generation) approaches. Here we describe the principles of computational antibody design and review the state of the art in this field. We then present Modular, a method that implements the rational rsc.li/chem-soc-rev design of antibodies in a modular manner, and describe the opportunities offered by this approach. Introduction heavy and light chains (Fig. 1). The tips of the Y are formed by the variable domains of the heavy (VH) and light (VL) chains, Antibodies and antibody fragments and contain the binding regions (paratopes). The paratopes are Antibodies are proteins produced by the immune system to usually located within six binding loops, three per variable target and neutralise pathogens and toxins. The binding of domain, which are referred to as the complementarity deter- antibodies to their target molecules, referred to as antigens, mining regions (CDRs), as they mediate the interaction with triggers their elimination by activating downstream processes the target regions of the antigens (epitopes). The base of in the immune response.
    [Show full text]
  • Paul Robustelli, Ph.D. Assistant Professor of Chemistry [email protected] Dartmouth College
    Paul Robustelli, Ph.D. Assistant Professor of Chemistry [email protected] Dartmouth College Professional Experience § Dartmouth College (Jan 2020–Present) § Assistant Professor of Chemistry § Member, Neukom Faculty Cluster of Computational Science § Member, Department of Biochemistry and Cell Biology § D.E. Shaw Research (2013-2019) Scientist § Developing Improved Physical Models for the Accurate Simulation of both Folded and Disordered Protein States § Elucidating Dynamic Binding Modes of Small Molecules with Intrinsically Disordered Proteins and Rationally Designing Tighter Binders § Columbia University Medical Center (2011-2013) NSF Postdoctoral Research Fellow § Mentor: Arthur G. Palmer III § Studying the Role of Conformational Dynamics in Protein Function with NMR Spectroscopy and Molecular Simulations § University of Cambridge, Department of Chemistry (2006-2011) Graduate Research Assistant § Mentor: Michele Vendruscolo § Development and Application of Novel Computational Methods for Protein Structure Determination from NMR Chemical Shifts § Pomona College, Department of Chemistry (2004-2006) Undergraduate Research Assistant § Mentor: Wayne E. Steinmetz § Determination of the Structure and Conformational Dynamics of Tricothecene Mycotoxins with NMR Spectroscopy and Molecular Modeling Education § University of Cambridge - Ph.D. in Chemistry (2010) § Dissertation Title: Protein Structure Determination from NMR Chemical Shifts § Supervisor: Michele Vendruscolo § Pomona College - B.A. in Chemistry with Minor in Mathematics
    [Show full text]
  • Towards Quantitative Predictions in Cell Biology Using Chemical Properties of Proteins Michele Vendruscolo and Gian Gaetano Tartaglia*
    HIGHLIGHT www.rsc.org/molecularbiosystems | Molecular BioSystems Towards quantitative predictions in cell biology using chemical properties of proteins Michele Vendruscolo and Gian Gaetano Tartaglia* DOI: 10.1039/b805710a It has recently been suggested that the concentrations of proteins in the cell are tuned towards their critical values, and that the alteration of this balance often results in misfolding diseases. This concept is intriguing because the in vivo concentrations of proteins are closely regulated by complex cellular processes, while their critical concentrations are primarily determined by the chemical characters of their amino acid sequences. We discuss here how the presence of a link between the upper levels of in vivo concentrations and critical concentrations offers an opportunity to make quantitative predictions in cell biology based on the chemical properties of proteins. Introduction: protein aggregation rates of the corresponding Solubility and chemical 7 chemistry and cell biology proteins measured in vitro (Fig. 2). properties of proteins In this highlight we explore the oppor- Cellular functions are orchestrated by tunities provided by the relationships be- The solubility of proteins can be defined complex regulatory networks involving tween the upper levels of in vivo in terms of their critical concentration, primarily nucleic acids and proteins.1,2 concentrations and the critical concentra- which is the concentration above which These same cellular functions are also, tions of proteins (Fig. 1) and between they form a condensed phase.9 The solu- however, dependent on the basic chem- mRNA expression levels and aggregation bility depends strongly on the thermo- istry of the molecules that carry them rates of the corresponding proteins (Fig.
    [Show full text]