Structure-based design of protein inhibitors requires the ability to predict conformational and free-energy changes occurring during protein-ligand binding. In principle this can be done by finding the conformation of lowest energy (global minimum) and the free-energy of the associated macrostate. But, in practice, the numerical complexity of the computation exceeds capabilities by many orders-of-magnitude. We are developing a new class of algorithms that uncovers and exploits the intrinsic hierarchical structure of macromolecular potential energy landscapes to thereby greatly increase the efficiency of this process. The approach, adapted from renormalization group methods which have been very successful in statistical physics, replaces conventional fixed-scale minimization and sampling with a sequence of operations at a series of decreasing size scales. During the past year we have developed much of the needed mathematical formalism and have performed tests on model systems including small peptides. We are currently extending our tests to larger peptides and developing the tools needed for application to larger proteins.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR004293-10
Application #
6411728
Study Section
Project Start
2000-12-01
Project End
2001-11-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
10
Fiscal Year
2001
Total Cost
$12,855
Indirect Cost
Name
Cornell University
Department
Type
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Chiang, Chi-Tung; Shores, Kevin S; Freindorf, Marek et al. (2008) Size-restricted proton transfer within toluene-methanol cluster ions. J Phys Chem A 112:11559-65
Kazmierkiewicz, Rajmund; Liwo, Adam; Scheraga, Harold A (2003) Addition of side chains to a known backbone with defined side-chain centroids. Biophys Chem 100:261-80
Kazmierkiewicz, Rajmund; Liwo, Adam; Scheraga, Harold A (2002) Energy-based reconstruction of a protein backbone from its alpha-carbon trace by a Monte-Carlo method. J Comput Chem 23:715-23
Liwo, Adam; Arlukowicz, Piotr; Czaplewski, Cezary et al. (2002) A method for optimizing potential-energy functions by a hierarchical design of the potential-energy landscape: application to the UNRES force field. Proc Natl Acad Sci U S A 99:1937-42
Scheraga, Harold A; Pillardy, Jaroslaw; Liwo, Adam et al. (2002) Evolution of physics-based methodology for exploring the conformational energy landscape of proteins. J Comput Chem 23:28-34
Scheraga, Harold A; Vila, Jorge A; Ripoll, Daniel R (2002) Helix-coil transitions re-visited. Biophys Chem 101-102:255-65
Pillardy, J; Czaplewski, C; Liwo, A et al. (2001) Recent improvements in prediction of protein structure by global optimization of a potential energy function. Proc Natl Acad Sci U S A 98:2329-33
Pillardy, J; Arnautova, Y A; Czaplewski, C et al. (2001) Conformation-family Monte Carlo: a new method for crystal structure prediction. Proc Natl Acad Sci U S A 98:12351-6
Vila, J A; Ripoll, D R; Scheraga, H A (2001) Influence of lysine content and pH on the stability of alanine-based copolypeptides. Biopolymers 58:235-46
Czaplewski, C; Rodziewicz-Motowidlo, S; Liwo, A et al. (2000) Molecular simulation study of cooperativity in hydrophobic association. Protein Sci 9:1235-45

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