Biology is at a stage where an understanding of the molecules involved in biological activity is an essential part of progress. Of particular importance are the various classes of biopolymers-- proteins, nucleic acids, saccharides, and lipids. All of these are complex systems; their individual properties and their interactions play a fundamental role in biology. The complexity is such that theoretical approaches are required to supplement the available experimental data. It is the aim of this proposal to use theoretical methods, in particular molecular dynamics simulations, to increase our knowledge of the properties of biopolymers and to use this knowledge to obtain a fundamental description of their function in specific cases of biological significance. The proposed research has as its initial aims: 1) To characterize by dynamical methods the nature of the underlying potential surface governing the internal motions of proteins in the neighborhood of the native structure and the transition between the native and denatured form. Simulated anneating will be used to examine the former and high temperature simulations with modified potentials the latter. 2) To characterize by dynamical and related methods the nature of ligand binding and dissociation in myoglobin and hemoglobin, with particular emphasis on the cooperative mechanism in the latter. Molecular dynamics, an adaptation of the time dependent Hartree method, and a new method for finding reaction paths will be utilized. 3) To investigate protein-nucleic acid interactions and their role in specific biological processes. Two DNA-protein systems, the lambdal repressor-operator system, and the EcoRI-DNA complex, for which X-ray structures suggest different binding motifs, will be investigated. Energy minimization, molecular and stochastic dynamics, and free energy simulations will be used. 4) To characterize the contributions of internal motions of biopolymers to their thermodynamic properties, such as the internal entropy of folded proteins and the entropic contribution to complex formation. Molecular dynamics and normal mode calculations will be used.
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| Nam, Kwangho; Verdine, Gregory L; Karplus, Martin (2009) Analysis of an anomalous mutant of MutM DNA glycosylase leads to new insights into the catalytic mechanism. J Am Chem Soc 131:18208-9 |
