Binding preferences of hydroxamate inhibitors of the matrix metalloproteinase human fibroblast collagenase

In this paper we report molecular dynamics (MD) and free energy perturbatio n (FEP) studies carried out on enzyme-inhibitor (two hydroxamates that only differ by a carbon-carbon double bond) complexes of human fibroblast colla genase to obtain insights into the structural and energetic preferences of these inhibitors. We have developed a bonded model for the catalytic and st ructural zinc centers (Hoops, S. C.; et al. J. Am. Chem. Sec. 1991, 113, 82 62-8270) where the electrostatic representation for this model was derived using a novel quantummechanical/molecular-mechanical (QM/MM) minimization p rocedure followed by electrostatic potential fitting. The resulting bonded model for the zinc ions was then used to generate MD trajectories for struc tural analysis and FEP studies. This model has satisfactorily reproduced th e structural features of the active site, and furthermore, the FEP simulati ons gave relative free energies of binding in good agreement with experimen tal results. MD simulations in conjunction with the FEP are able to provide a structural explanation regarding why one hydroxamate inhibitor is favore d over the other, and we are also able to make predictions about changes in the inhibitor that would enhance protein-inhibitor interactions.