Systematic Derivation of AMBER Force Field Parameters Applicable to Zinc-Containing Systems

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Abstract

Metal ions are indispensable for maintaining the structural stability and catalytic activity of metalloproteins. Molecular modeling studies of such proteins with force fields, however, are often hampered by the "missing parameter" problem. In this study, we have derived bond-stretching and angle-bending parameters applicable to zinc-containing systems which are compatible with the AMBER force field. A total of 18 model systems were used to mimic the common coordination configurations observed in the complexes formed by zinc-containing metalloproteins. The Hessian matrix of each model system computed at the B3LYP/6-311++G(2d,2p) level was then analyzed by Seminario's method to derive the desired force constants. These parameters were validated extensively in structural optimizations and molecular dynamics simulations of four selected model systems as well as one protein-ligand complex formed by carbonic anhydrase II. The best performance was achieved by a bonded model in combination with the atomic partial charges derived by the restrained electrostatic potential method. After some minor optimizations, this model was also able to reproduce the vibrational frequencies computed by quantum mechanics. This study provides a comprehensive set of force field parameters applicable to a variety of zinc-containing molecular systems. In principle, our approach can be applied to other molecular systems with missing force field parameters.

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