Modeling the function of biological systems is a major conceptual and computational challenge . Using fully atomistic models with rigorous simulation treatments might prevent one from reaching clear conclusions about the action of the given system , whereas the construction of oversimplified models without sufficient physical basis might lead to irrelevant conclusions .
This talk will review our progress in multiscale modeling, emphasizing the physical reality and the connection between the different modeling levels. We will start with a brief description of simplified folding models ( 1) ,which are perhaps the first examples of multiscale modeling in studies of proteins, and describe a connection between the simplified and the all atom models (2) . We will then consider very briefly QM/MM calculations ( 3,4) of proteins, which also provide examples of multi scale studies. Next we will move to the main topic, which will be the demonstration of the use of consistent multiscale modeling of ion current in ion channels and of the action of proton pumps. In both cases we will explain how can one moves from a fully atomistic microscopic treatment ( sometimes with quantum mechanical elements) to semimacroscopic free energy surfaces and eventually to Brownian Dynamics or Monte Carlo simulations of slow events (5,8). We will thus provide examples of consistent simulations of millisecond biological processes using various multiscale strategies.
References:
(1) Computer Simulations of Protein Folding, M. Levitt and A. Warshel, Nature 253, 694 (1975).
(2) Using Simplified Protein Representation as a Reference Potential for All-Atom Calculations of Folding Free Energy, Z.Z. Fan, J.-K. Hwang and A. Warshel, Theor. Chem. Acc. 103, 77 (1999).
(3) Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme, A. Warshel and M. Levitt, J. Mol. Biol. 103, 227 (1976).
(4) Structure/Function Correlations of Enzymes using MM, QM/MM and Related Approaches; Methods, Concepts, Pitfalls and Current Progress, A. Shurki and A. Warshel., Advances in Protein Chemistry, 66,249-313 (2003).
(5) Exploring the origin of the ion selectivity of the KcsA potassium channel, A. Burykin , M. Kato and A. Warshel, PROTEINS Structure, Function and Genetics, 52, 412-426 (2003).
(6) Simulating Proton Translocations in Proteins: Probing Proton Transfer Pathways in the Rhodobacter sphaeroides Reaction Center, Y.Y. Sham, I. Muegge and A. Warshel, Proteins: Structure, Function and Genetics, 36, 484-500 (1999).
(7) Studies of Proton Translocations in Biological Systems: Simulating Proton Transport in Carbonic Anhydrase by EVB Based Models, S. Braun-Sand, M. Strajbl, and A. Warshel. Biophys. J.87,2221-2239, (2004).
(8) Simulating Redox Coupled Proton Transfer in Cytochrome c Oxidase; Looking for the Proton Bottleneck,M. H. M. Olsson, P. K. Sharma and A. Warshel, FEBS letters,579,2026-2034 (2005)
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