title: Binding and discerning interactions of PTP1B allosteric inhibitors: novel insights from molecular dynamics simulations.
abstract: The α7 helix is either disordered or missing in the three co-crystal structures of allosteric inhibitors with protein tyrosine phosphatase 1B (PTP1B). It was modeled in each complex using the open form of PTP1B structure and studied using molecular dynamics (MD) simulations for 25 ns. B-factor analysis of the residues sheds light on its disordered nature in the co-crystal structures. Further, the ability of inhibitors to act as allosteric inhibitor was studied and established using novel hydrogen bond criteria. The MD simulations were utilized to determine the relative importance of electrostatic and hydrophobic component in to the binding of inhibitors. It was revealed that the hydrophobic interactions predominantly drive the molecular recognition of these inhibitors. Per residue energy decomposition analysis attributed dissimilar affinities of three inhibitors to the several hydrogen bonds and non-bonded interactions. Among the secondary structure elements that surround the allosteric site, helices α6, α7 and loop α6-α7 were notorious in providing variable affinities to the inhibitors. A novel hydrophobic pocket lined by the α7 helix residues Val287, Asn289 and Trp291 was identified in the allosteric site. This study provides useful insights for the rational design of high affinity PTP1B allosteric inhibitors.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Ranajit Nivrutti
authors.initials: RN
authors.lastname: Shinde
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Sobhia
mesh_terms: D000495:Allosteric Site; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Allosteric inhibition; B-factor; Binding free energy; Hydrogen bond; Molecular modeling; Per-residue energy decomposition