The overall rationale of the research in our laboratory is to discover structural, dynamic and electronic determinants of biological processes that underlie physiological functions, using methods of theoretical and computational biophysics. We seek a molecular level, mechanistic understanding of structure-function relationships anchored in experimental information about structures and properties of cellular components and physiological mechanisms. Our approaches use well-defined algorithms based on the fundamental laws of classical and quantum physics; they include computer assisted modeling of molecular structure and properties and computational simulations of molecular mechanisms. The theoretical studies are designed to complement experimentation in providing mechanistic insights about systems of ever increasing size and complexity, and to guide pointed experimental exploration of cellular processes and functions in numerous collaborative studies. To facilitate the interaction between the theoretical and experimental studies, the projects described below are carried out in close collaboration with experimental groups. The theoretical methods we use are also being expanded, refined and tested in the study of biomolecular systems. The goals of these methodological developments are to extend the scope of problems that can be studied by computational approaches, deepen the insights that can be obtained from the computations with novel and sophisticated methods of analysis, and allow the fast calculation of properties that are of direct experimental relevance. As documented in our publications, our work addresses major areas of current research. A unifying theme in our studies of diverse biological processes is to achieve a molecular understanding of mechanisms triggered by molecular recognition and leading to signal transduction. Currently, we study structural specificity and dynamics in three main areas in which such processes determine essential physiological mechanisms as follows: i) The determinants of specificity in mechanisms of cellular signaling through ligand recognition and receptor response; ii) the decoding and processing of Ca2+ signals through the EF-hand Ca-binding proteins; and iii) the specificity and functional trigger produced by protein binding to DNA. A fourth area comprises the formulation and development of an implicit solvent model for fast computer simulations of biological systems.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Cornell University
United States
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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; 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
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
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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