| Abstract
| - In this paper we report molecular dynamics (MD) and free energy perturbation (FEP) studiescarried out on enzyme−inhibitor (two hydroxamates that only differ by a carbon−carbon doublebond) complexes of human fibroblast collagenase to obtain insights into the structural andenergetic preferences of these inhibitors. We have developed a bonded model for the catalyticand structural zinc centers (Hoops, S. C.; et al. J. Am. Chem. Soc. 1991, 113, 8262−8270)where the electrostatic representation for this model was derived using a novel quantum-mechanical/molecular-mechanical (QM/MM) minimization procedure followed by electrostaticpotential fitting. The resulting bonded model for the zinc ions was then used to generate MDtrajectories for structural analysis and FEP studies. This model has satisfactorily reproducedthe structural features of the active site, and furthermore, the FEP simulations gave relativefree energies of binding in good agreement with experimental results. MD simulations inconjunction with the FEP are able to provide a structural explanation regarding why onehydroxamate inhibitor is favored over the other, and we are also able to make predictionsabout changes in the inhibitor that would enhance protein−inhibitor interactions.
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