Assistant Professor in Experimental Biological Physics
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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. -
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. -
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 -
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. -
Nanog Induced Intermediate State in Regulating Stem Cell Differentiation and Reprogramming
UC Irvine UC Irvine Previously Published Works Title Nanog induced intermediate state in regulating stem cell differentiation and reprogramming. Permalink https://escholarship.org/uc/item/3xw9t7g5 Journal BMC systems biology, 12(1) ISSN 1752-0509 Authors Yu, Peijia Nie, Qing Tang, Chao et al. Publication Date 2018-02-27 DOI 10.1186/s12918-018-0552-3 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Yu et al. BMC Systems Biology (2018) 12:22 https://doi.org/10.1186/s12918-018-0552-3 RESEARCH ARTICLE Open Access Nanog induced intermediate state in regulating stem cell differentiation and reprogramming Peijia Yu1, Qing Nie2*, Chao Tang1,3* and Lei Zhang1,4* Abstract Background: Heterogeneous gene expressions of cells are widely observed in self-renewing pluripotent stem cells, suggesting possible coexistence of multiple cellular states with distinct characteristics. Though the elements regulating cellular states have been identified, the underlying dynamic mechanisms and the significance of such cellular heterogeneity remain elusive. Results: We present a gene regulatory network model to investigate the bimodal Nanog distribution in stem cells. Our model reveals a novel role of dynamic conversion between the cellular states of high and low Nanog levels. Model simulations demonstrate that the low-Nanog state benefits cell differentiation through serving as an intermediate state to reduce the barrier of transition. Interestingly, the existence of low-Nanog state dynamically slows down the reprogramming process, and additional Nanog activation is found to be essential to quickly attaining the fully reprogrammed cell state. -
1. Brief Introduction to the Institute of Geology
-1- The Institute of Geology, Chinese Academy of Geological Sciences (CAGS) Preface The Institute of Geology, Chinese Academy of Geological Sciences (CAGS), is a national public scientific research institution and is mainly engaged in national fundamental, public, strategic and frontier geological survey and geoscientific research. Entering the new century, and in particular during the past 5 years, the Institute has made notable progress in scientific research, personnel training and international cooperation, with increasing cooperation and exchange activities, expanded fields of cooperation, abundant output of new research results, and an increased number of papers published in “Nature”, “Science” and other high-impact international scientific journals. In the light of this new situation and in order to publicize, in a timely manner, annual progress and achievements of the Institute to enhance its international reputation, an English version of the Institute’s Annual Report has been published since 2010. Similar to previous reports, the Annual Report 2015 includes the following 7 parts: (1) Introduction to the Institute of Geology, CAGS; (2) Ongoing Research Projects; (3) Research Achievements and Important Progress; (4) International Cooperation and Academic Exchange; (5) Important Academic Activities in 2015; (6) Postgraduate Education; (7) Publications. In order to avoid confusion in the meaning of Chinese and foreign names, all family names in this Report are capitalized. We express our sincere gratitude to colleagues of related research departments and centers of the Institute for their support and efforts in compiling this Report and providing related material – a written record of the hard work of the Institute’s scientific research personnel for the year 2015. -
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). -
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. -
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. -
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. -
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 -
The University of Chicago-Educated Chinese Phds of 1915-1960
The Untold Stories: The University of Chicago-educated Chinese PhDs of 1915-1960 Frederic Xiong* ------------------------------------------------------------------------------------------------------------------------------ Abstract In modern Chinese history, there have been three major waves of Chinese students going to study in the United States. The second wave began in the late 19th century and continued up to 1960. Through political turmoil, two Sino-Japanese Wars, the Chinese Civil War, the regime-change in 1911, the Communists’ victory in 1949, and Korean War, 2,455 Chinese students earned Doctorates of Philosophy (PhD) degrees from 116 American colleges and universities. The University of Chicago (UChicago), a prestigious research university, educated 142 of those students, the fourth highest number among universities in the U.S. This paper presents the first comprehensive list of Chinese scholars awarded PhDs at UChicago from 1915 to 1960, as well as descriptions of their achievements and what they did after graduation. It also explores the lives of Chinese PhDs who chose to stay in the U.S., as well as those who returned to China after the Communists came to power. Those who stayed in the U.S. later helped China when it reopened its borders to outside of the world. Those who returned to China suffered greatly during the political upheavals—especially the Cultural Revolution, in which at least a dozen lost their lives. PART I Chinese Students Studying in the U.S. In modern Chinese history, there have been three major waves of Chinese students going to study in the U.S. The first wave can be traced back to 1847 when Yung Wing (容闳, 1828-1912) became the first Chinese student to study in the U.S.