title: 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.
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Sharad
authors.initials: S
authors.lastname: Verma
authors.affiliation: Department of Biotechnology, TERI University, Vasant Kunj, New Delhi 110 070, India.
authors.forename: Aditi
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Biotechnology, TERI University, Vasant Kunj, New Delhi 110 070, India.
authors.forename: Anchala
authors.initials: A
authors.lastname: Kumari
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: Department of Biotechnology, TERI University, Vasant Kunj, New Delhi 110 070, India.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sinha
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: abhinavgr@gmail.com.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D053818:Chymases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis
chemical_list: D004791:Enzyme Inhibitors; D053818:Chymases
keywords: Chymase; Free energy decomposition; MM/PBSA; Molecular dynamics simulation; Mutation