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Kinetic and binding effects in peptide substrate selectivity of matrix metalloproteinase‐2: Molecular dynamics and QM/MM calculations
Author(s) -
Díaz Natalia,
Suárez Dimas,
Suárez Ernesto
Publication year - 2010
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22493
Subject(s) - peptide , molecular dynamics , chemistry , substrate (aquarium) , computational chemistry , molecular mechanics , stereochemistry , active site , hydrolysis , enzyme , combinatorial chemistry , enzyme kinetics , binding energy , kinetic energy , organic chemistry , biochemistry , physics , oceanography , quantum mechanics , geology , nuclear physics
Herein, we examine computationally the binding and hydrolysis reaction of the MMP‐2 enzyme with two peptide substrates selected by the enzyme from a phage peptide library. Molecular dynamics simulations of the Michaelis complexes (25 ns) allow us to characterize the main enzyme/substrate contacts. Subsequently MM‐PBSA calculations using independent trajectories for the complexes and the free substrates provide relative binding energies in good agreement with the experimental K M results. Computational alanine scanning analyses of the enzyme/substrate interaction energies confirm the relevance of the P 3 , P 2 , and P 1 ′ side chains for ligand binding. Finally, the hydrolysis of both peptides taking place at the MMP‐2 active site is explored by means of hybrid quantum mechanical/molecular mechanics calculations. The computed reaction mechanisms result in rate‐determining energy barriers being in consonance with the experimental k cat values. Overall, the computational protocol seems to capture the subtle differences in binding and catalysis experimentally observed for the two peptide substrates. Some implications of our results for the future design of novel and more specific MMP‐2 inhibitors are also discussed. Proteins 2010. © 2009 Wiley‐Liss, Inc.