title: Molecular dynamics simulations reveal structural insights into inhibitor binding modes and functionality in human Group IIA phospholipase A2.
abstract: Human Group IIA phospholipase A2(hGIIA) promotes inflammation in immune-mediated pathologies by regulating the arachidonic acid pathway through both catalysis-dependent and -independent mechanisms. The hGIIA crystal structure, both alone and inhibitor-bound, together with structures of closely related snake-venom-derived secreted phospholipase enzymes has been well described. However, differentiation of biological and nonbiological contacts and the relevance of structures determined from snake venom enzymes to human enzymes are not clear. We employed molecular dynamics (MD) and docking approaches to understand the binding of inhibitors that selectively or nonselectively block the catalysis-independent mechanism of hGIIA. Our results indicate that hGIIA behaves as a monomer in the solution environment rather than a dimer arrangement that is in the asymmetric unit of some crystal structures. The binding mode of a nonselective inhibitor, KH064, was validated by a combination of the experimental electron density and MD simulations. The binding mode of the selective pentapeptide inhibitor FLSYK to hGIIA was stipulated to be different to that of the snake venom phospholipases A2of Daboia russelli pulchella (svPLA2). Our data suggest that the application of MD approaches to crystal structure data is beneficial in evaluating the robustness of conclusions drawn based on crystal structure data alone. Proteins 2017; 85:827-842. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Ryung Rae
authors.initials: RR
authors.lastname: Kim
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia, 4072.
authors.forename: Alpeshkumar K
authors.initials: AK
authors.lastname: Malde
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Alireza
authors.initials: A
authors.lastname: Nematollahi
authors.affiliation: School of Medicine, Western Sydney University, The Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia, 2170.|Centre for Oncology Education and Research Translation (CONCERT), The Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia, 2170.
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Scott
authors.affiliation: Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: W Bret
authors.identifier: 0000-0002-8033-5518
authors.initials: WB
authors.lastname: Church
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D004583:Electrons; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry*; D010421:Pentanoic Acids / Q000737:chemistry*; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry*; D054467:Phospholipases A2 / Q000737:chemistry; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D014757:Viper Venoms / Q000737:chemistry; D017819:Viperidae / Q000378:metabolism
chemical_list: C503211:5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)pentanoic acid; D009842:Oligopeptides; D010421:Pentanoic Acids; D064801:Phospholipase A2 Inhibitors; D014757:Viper Venoms; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human; D054467:Phospholipases A2
keywords: FLSYK inhibitor; Group IIA phospholipase A2; binding site; docking; molecular dynamics; protein-protein interaction; vimentin