Dissecting the role of mutations in chymase inhibition: Free energy and decomposition analysis

Abstract

Chymase enzyme abundantly found in secretory granules of mast cells and catalyzes the hydrolysis of peptide bonds to generate angiotensin II via hydrolysis of angiotensin I and also activates transforming growth factor-b and MMP-9. MMP-9 and TGF-b have significant role in tissue inflammation and fibrosis. In present study, we investigated that Lys192Met mutation leads to a higher loss in binding energy of inhibitors than mutation Arg143Gln in chymase. The energy decomposition revealed that the contributing residues are almost same in all the forms with some change in energy value. All the results pointing that arginine and lysine residues of chymase play the most significant role in inhibitor binding revealed by energy decomposition. The Lys40, Arg90, Lys192 and Arg217 are found to be most prominent residues in two different inhibitor systems but the role of other lysine and arginine also important as they also have significant contribution in the total binding energy.

Keywords: Chymase; Free energy decomposition; MM/PBSA; Molecular dynamics simulation; Mutation.