Research

I. Binding specificity of SH2 domains

The SH2 domain (cartoon, green) from human p56-lck tyrosine kinase bound with a short peptide pYEEI (stick). PDB code: 1LKK, figure generated by PyMol

SH2 domains are a family of modular interaction domains that are present in a wide variety of signaling molecules, such as protein kinases, protein phosphatases, protein phospholipases, transcription factors, signal regulator proteins, adaptor proteins, scaffold proteins et al. Functionally, SH2 domains specifically bind phosphotyrosine(pY)-containing motifs within their target proteins. What's more remarkable about SH2 domains is that they recognize specific residues C-terminal to phosphotyrosine in a way that varies from one SH2 domain to another. For instance, Src kinase SH2 domain binds pYEEI motif, whereas Grb2 SH2 domain prefers pYVNV motif. We have studied the binding specificity of five representative SH2 domains (PDB code: 1LKK, 1JYR, 2CBL, 2IUH, 1YVL) by computing absolute binding free energies and directly comparing the affinities of a given SH2 domain binding with distinct peptides. Read more ...

II. Conformational change of c-Src tyrosine kinase

Catalytical domain of c-Src tyrosine kinase in the inactive state. PDB code: 2SRC, figure generated by PyMol

Src tyrosine kinases are a family of enzymes that catalyze the transfer of ATP gamma-phosphate to protein tyrosine residues. The catalytical activity of Src kinase is modulated by specific signals and activation event is accompanied with large conformational changes. Although both the active and inactive forms of c-Src tyrosine kinase have been crystallized (PDB code: 2SRC /1Y57), little is known about the molecular details of this complex conformational transition and the free energy landscape that governs the transition. Also, on what timescale this conformational transition happens is not clear to date. We are trying to address these important questions by using a variety of computational techniques including string method, umbrella sampling PMF calculations and Markov state models. Preliminary results can be found here.

III. Folding pathways of villin headpiece subdomain HP35

Villin headpiece subdomain HP35 in the folded native state. PDB code: 1YRF, figure generated by VMD

One of the challenges in studying protein folding is to understand the folding mechanism at atomic resolution. Arguably, all-atom MD simulations provides the most detailed information about the folding and unfolding process. However, the gap between the timescale of brute-force MD simulations, usually on the order of ns, and that of biologically important folding process, mostly ranging from microseconds to seconds, severely limits the application of MD simulation to folding study. Therefore, attempt to speedup protein folding simulations is of great interest. We choose the 35-residue villin headpiece subdomain HP35 (PDB code: 1YRF) as a model system because it is a fast-folding protein domain that has been well studied. Our goal is to identify representative folding pathway by the string method, map out the one-dimensional free energy profile along the pathway, estimate the folding timescale and compare with other experimental and computational studies.

Links

  


1. Online Journals

   Annual Reviews Biochemistry Biophysical J Cell Chem Phys Lett Curr Opin Struct Biol

   J A C S J Chem Phys J C T C J Comp Chem J Mol Biol J Phys Chem B

   Nature Nat Struct Mol Biol Phys Rev Lett PLOS Comp Biol P N A S Protein Sci

   Proteins Science Structure

   
     
   
   
2. Computational Biophysics List
   This list is intended for people who are looking for undergrad summer research opportunities, places to start their PhDs, postdoc positions, or research collaborations. If your research is in the field of theoretical & computational biophysics and you want your group to be included in the list, or if your group has moved and the following link no longer works, please send an email to gan-at-uchicago-dot-edu

   Toby W. Allen, UC Davis Ioan Andricioaei, UC Irvine David Baker, University of Washington Nathan A. Baker, Washington University Nilesh K. Banavali, Wadsworth Center Bruce Berne, Columbia University Robert Best, University of Cambridge Ivet Bahar, University of Pittsburgh Peter Bolhuis, University of Amsterdam Stephen Bond, UIUC James M. Briggs, University of Houston Frank Brown, UCSB Bernard R. Brooks, NIH Charlie L. Brooks III, University of Michigan Heather A. Carlson, University of Michigan David A. Case, Rutgers University Arup K. Chakraborty, MIT David Chandler, UC Berkeley Thomas E. Cheatham, III, University of Utah Jhih-Wei Chu, UC Berkeley Giovanni Ciccotti, University of Rome Cecilia Clementi, Rice University Qiang Cui, University of Wisconsin William F. DeGrado, UPenn Ken A. Dill, UCSF Aaron R. Dinner, University of Chicago Yong Duan, UC Davis Weinan E, Princeton Ron Elber, UT Austin Adrian Elcock, University of Iowa Jose Faraldo-Gomez, Max Planck Institute Michael Feig, Michigan State University Scott Feller, Wabash College Merrell R. Fenske, Penn State Karl F. Freed, University of Chicago Daan Frenkel, University of Cambridge Richard A. Friesner, Columbia University Jiali Gao, University of Minnesota Yiqin Gao, Texas A&M University Angel E. Garcia, RPI Phillip Geissler, UC Berkeley Michael K. Gilson, University of Maryland Michael Hagan, Brandeis University Teresa Head-Gordon, UC Berkeley Graeme Henkelman, UT Austin Nina Singhal Hinrichs, University of Chicago Barry Honig, Columbia University Kendall N. Houk, UCLA Gerhard Hummer, NIH Wonpil Im, University of Kansas Matt Jacobson, UCSF William L. Jorgensen, Yale University Martin Karplus, Harvard University Dorothee Kern, Brandeis University Michael L. Klein, UPenn Peter A. Kollman, UCSF John Kuriyan, UC Berkeley Ronald M. Levy, Rutgers University

   Luhua Lai, Peking University Jianpeng Ma, Baylor College of Medicine Alex D. Mackerell Jr., University of Maryland Stephen L. Mayo, Caltech J. Andrew McCammon, UCSD Thomas Miller, Caltech Frank Noe, Free University of Berlin Sergei Noskov, University of Calgary Ruth Nussinov, NIH Jose Onuchic, UCSD Vijay Pande, Stanford University Michele Parrinello, ETH Zurich Richard Pastor, NIH Sandeep Patel, University of Delaware Baron Peters, UCSB B. Montgomery Pettitt, University of Houston Jay Ponder, Washington University Carol B. Post, Purdue University Lawrence R. Pratt, Tulane University Pengyu Ren, UT Austin Adrian Roitberg, University of Florida Benoit Roux, University of Chicago Andrej Sali, UCSF Mark S.P. Sansom, University of Oxford Harold Scheraga, Cornell University Sharon Hammes-Schiffer, Penn State Tamar Schlick, New York University Christof Schuette, Free University of Berlin Klaus J. Schulten, UIUC David Sept, Washington University Carlos Simmerling, SUNY Stony Brook Eugene Shakhnovich, Harvard University David E. Shaw, D. E. Shaw Research James L. Skinner, University of Wisconsin Harry A. Stern, University of Rochester John E. Straub, Boston University Devarajan Thirumalai, University of Maryland Bruce Tidor, MIT D. Peter Tieleman, University of Calgary Douglas J. Tobias, UC Irvine Bernhardt L. Trout, MIT Donald G. Truhlar, University of Minnesota Mark E. Tuckerman, New York University Wilfred van Gunsteren, ETH Zurich Eric Vanden-Eijnden, New York University Gregory A. Voth, University Utah Arthur F. Voter, Los Alamos National Lab Jin Wang, SUNY Stony Brook Wei Wang, UCSD Arieh Warshel, University of Southern California Stephen H. White, UC Irvine Benjamin Widom, Cornell University Peter Wolynes, UCSD Hyung-June Woo, University of Nevada Reno Tom Woolf, JHU Wei Yang, Florida State University Yingkai Zhang, New York University Yaoqi Zhou, Indiana University

   
     
   
   
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