Effect of solvation water shells on enzyme active sites in zinc-dependent hydrolases

In this work, we focus on some structural aspects of enzyme catalysis by modeling effects of the electrostatic potential created by the solvation water shells on properties of enzyme-substrate (ES) complexes. We simulate structure and dynamics of shells of explicit water molecules around two zinc-dependent hydrolases, matrix metalloproteinase-2 and metallo-β-lactamase, using classical force field parameters. Geometry configurations of the ES complexes for both systems are taken from the results of quantum mechanics/molecular mechanics (QM/MM) calculations. Evaluation of the electrostatic potentials from water molecules acting on selected points in the enzyme active sites shows that the shape and the size of solvent shells are important when simulating properties of reacting species inside a protein. We show that a practical way to construct the water shells around the protein is to include all external waters molecules located within the sphere centered at the center of mass of the ES complex or select a water layer around the protein of a constant thickness. In these cases, the computed electrostatic potentials on the selected points in the active site show a reasonable convergence with respect to the size of the solvation shell. We show that the analysis of the fluctuating electrostatic potentials is helpful in selecting the average structures of ES complexes, from which the reaction energy profiles should be computed.