The functioning of living organisms is largely dependent on the fact that each of its constituent proteins adopts a unique structure (the so-called native structure) under physiological conditions; this structure is determined by amino-acid sequence and its environment. According to Anfinsen's thermodynamic hypothesis, the native conformation of a protein is a global-energy minimum on its free-energy hypersurface. The native structure can therefore be sought as the global minimum in this hypersurface, if an accurate potential energy function is available. The shape of the free-energy hypersurface of proteins is very complex and difficult to describe. For efficiency reasons, simplified models of polypeptide chains, in which each amino-acid residue is represented by one or a few interaction sites rather than all-atom resolution models, must be used. While our previous focus was on global optimization methods, it is now focused on our physics-based united-residue UNRES potential-energy function. The main goal is to predict the structure of proteins of all major structural classes (alpha, beta, alpha+beta and alpha/beta) with chain lengths of up to 200 amino-acid residues within 4-6 Angstrom root mean square deviation based solely on global optimization of the potential energy. This will be accomplished by improving the functional forms and parameters of individual energy components and assuring the folding property of the potential by optimizing the total energy function to reflect the energetic hierarchy of partially unfolded structures. Understanding of the role of physical interactions in the formation of the native structur e of the protein will enable us not only to predict the final structure of the protein based only on knowledge of the amino-acid sequence but can be used to study protein folding or misfolding processes. The ability to predict three-dimensional structures of proteins or to predict their folding pathways can greatly contribute to rational drug design against cancer, Alzheimer or prion deseases.

National Institute of Health (NIH)
Fogarty International Center (FIC)
Small Research Grants (R03)
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International and Cooperative Projects 1 Study Section (ICP)
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Michels, Kathleen M
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Cornell University
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Maisuradze, Gia G; Liwo, Adam; Scheraga, Harold A (2009) Principal component analysis for protein folding dynamics. J Mol Biol 385:312-29
Liwo, Adam; Czaplewski, Cezary; Oldziej, Stanislaw et al. (2008) Computational techniques for efficient conformational sampling of proteins. Curr Opin Struct Biol 18:134-9
Kleinerman, Dana S; Czaplewski, Cezary; Liwo, Adam et al. (2008) Implementations of Nose-Hoover and Nose-Poincare thermostats in mesoscopic dynamic simulations with the united-residue model of a polypeptide chain. J Chem Phys 128:245103
Makowski, Mariusz; Sobolewski, Emil; Czaplewski, Cezary et al. (2008) Simple physics-based analytical formulas for the potentials of mean force for the interaction of amino acid side chains in water. IV. Pairs of different hydrophobic side chains. J Phys Chem B 112:11385-95
Sobolewski, Emil; Makowski, Mariusz; Czaplewski, Cezary et al. (2007) Potential of mean force of hydrophobic association: dependence on solute size. J Phys Chem B 111:10765-74
Murarka, Rajesh K; Liwo, Adam; Scheraga, Harold A (2007) Separation of time scale and coupling in the motion governed by the coarse-grained and fine degrees of freedom in a polypeptide backbone. J Chem Phys 127:155103
Makowska, Joanna; Rodziewicz-Motowidlo, Sylwia; Baginska, Katarzyna et al. (2007) Further evidence for the absence of polyproline II stretch in the XAO peptide. Biophys J 92:2904-17
Scheraga, Harold A; Khalili, Mey; Liwo, Adam (2007) Protein-folding dynamics: overview of molecular simulation techniques. Annu Rev Phys Chem 58:57-83
Makowski, Mariusz; Sobolewski, Emil; Czaplewski, Cezary et al. (2007) Simple physics-based analytical formulas for the potentials of mean force for the interaction of amino acid side chains in water. 3. Calculation and parameterization of the potentials of mean force of pairs of identical hydrophobic side chains. J Phys Chem B 111:2925-31
Liwo, Adam; Khalili, Mey; Czaplewski, Cezary et al. (2007) Modification and optimization of the united-residue (UNRES) potential energy function for canonical simulations. I. Temperature dependence of the effective energy function and tests of the optimization method with single training proteins. J Phys Chem B 111:260-85

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