title: Comparative analysis of binding sites of human meprins with hydroxamic acid derivative by molecular dynamics simulation study.
abstract: Meprins are complex and highly glycosylated multi-domain enzymes that require post-translational modifications to reach full activity. Meprins are metalloproteases of the astacin family characterized by a conserved zinc-binding motif (HExxHxxGFxHExxRxDR). Human meprin-α and -β protease subunits are 55% identical at the amino acid level, however the substrate and peptide bond specificities vary markedly. Current work focuses on the critical amino acid residues in the non-primed subsites of human meprins-α and -β involved in inhibitor/ligand binding. To compare the molecular events underlying ligand affinity, homology modeling of the protease domain of humep-α and -β based on the astacin crystal structure followed by energy minimization and molecular dynamics simulation of fully solvated proteases with inhibitor Pro-Leu-Gly-hydroxamate in S subsites were performed. The solvent accessible surface area curve shows a decrease in solvent accessibility values at specific residues upon inhibitor binding. The potential energy, total energy, H-bond interactions, root mean square deviation and root mean square fluctuation plot reflect the subtle differences in the S subsite of the enzymes which interact with different residues at P site of the inhibitor.
authors.affiliation: a Department of Microbiology , West Bengal State University , Barasat, Berunanpukuria, P.O. Malikapur, North 24 Parganas, Kolkata 700126 , West Bengal , India.
authors.forename: Ankur
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Indrani
authors.initials: I
authors.lastname: Sarkar
authors.forename: Sibani
authors.initials: S
authors.lastname: Chakraborty
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000737:chemistry*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D055550:Protein Stability; D020539:Sequence Analysis, Protein; D008625:Tiopronin / Q000737:chemistry*
chemical_list: D006877:Hydroxamic Acids; D008024:Ligands; D008625:Tiopronin
keywords: hydroxamic acid derivative; simulation; solvent accessibility; subsites; α- and β-meprins