Binding affinity of hydroxamate inhibitors of matrix metalloproteinase-2.
Here we report molecular dynamics (MD) and free energy perturbation (FEP) simulations applied to hydroxamate-matrix metalloproteinase-2 (MMP-2) complex systems. We have developed some new force field parameters for the hydroxamate functional group that were not included in the AMBER94 force field but were necessary in our simulations. For the representation of the active zinc center, a bonded model was adopted in which restrained electrostatic potential fitting (RESP) charges were used as the electrostatic representation of this model. Using the resulted bonded model, FEP simulations predict the relative binding free energy in good agreement with the experimental value. By analyzing the molecular dynamics (MD) trajectories of the two complex systems, we can provide an explanation of why one of the two inhibitors is favored over the other. The results provide a chemical insight into the interactions between inhibitor and enzyme, and can indicate changes in the inhibitor that would enhance inhibitor-enzyme interactions.
Zhang
Wei
W
College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, People's Republic of China.
Hou
Ting-Jun
TJ
Qiao
Xue Bin
XB
Huai
Sun
S
Xu
Xiao Jie
XJ
D000577:Amides / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D055672:Static Electricity; D015032:Zinc / Q000737:chemistry
C510177:5-aza-6-cyclohexylmethyl-3-cyclohexylpropyl-4,7-dioxo-7-(phenylethylamino)heptanohydroxamic acid; C510178:5-aza-6-cyclohexylmethyl-4,7-dioxo-7-(phenylethylamino)-3-phenylpropylheptanohydroxamic acid; D000577:Amides; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D015032:Zinc