Molecular dynamics (MD) and free energy perturbation (FEP) studies were carried out on two enzyme-inhibitor complex of human Matrix Metalloproteinase-3 to obtain energy preference of the two inhibitors. We have developed a bonded model for the catalytic zinc center (including histidine and hydroxamate inhibitor that coordinated with catalytic zinc), where the charge of this model was derived using a two-step electrostatic potential fitting. Both slow growth method and fixed width window growth method with double-wide sampling were used in our simulations, it reproduced the structure feature well and the calculated relative free energy made a good agreement with experimental result. MD trajectories gave the binding mode between MMP-3 and hydroxamates, the P1 subunit of the inhibitor made a good van der Wall's contacts with the receptor's S1' substituent. In particular, the benzene ring on P1 could form a staking interaction with the π-face of Tyr223.

Key words: FREE ENERGY, PERTURBATION THEORY, INHIBITOR, HYDROLASE, ZINC COMPOUNDS