title: Docking and molecular dynamics simulations of the Fyn-SH3 domain with free and phospholipid bilayer-associated 18.5-kDa myelin basic protein (MBP)-Insights into a noncanonical and fuzzy interaction.
abstract: The molecular details of the association between the human Fyn-SH3 domain, and the fragment of 18.5-kDa myelin basic protein (MBP) spanning residues S38-S107 (denoted as xα2-peptide, murine sequence numbering), were studied in silico via docking and molecular dynamics over 50-ns trajectories. The results show that interaction between the two proteins is energetically favorable and heavily dependent on the MBP proline-rich region (P93-P98) in both aqueous and membrane environments. In aqueous conditions, the xα2-peptide/Fyn-SH3 complex adopts a "sandwich""-like structure. In the membrane context, the xα2-peptide interacts with the Fyn-SH3 domain via the proline-rich region and the β-sheets of Fyn-SH3, with the latter wrapping around the proline-rich region in a form of a clip. Moreover, the simulations corroborate prior experimental evidence of the importance of upstream segments beyond the canonical SH3-ligand. This study thus provides a more-detailed glimpse into the context-dependent interaction dynamics and importance of the β-sheets in Fyn-SH3 and proline-rich region of MBP. Proteins 2017; 85:1336-1350. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Systems and Modeling Unit, Montefiore Institute, Université de Liège, Quartier Polytech 1, Allée de la Découverte 10, Liège, 4000, Belgium.
authors.forename: Kyrylo
authors.initials: K
authors.lastname: Bessonov
authors.affiliation: Department of Molecular and Cellular Biology, Biophysics Interdepartmental Group, and Collaborative Program in Neuroscience, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada.
authors.forename: Kenrick A
authors.initials: KA
authors.lastname: Vassall
authors.affiliation: Department of Molecular and Cellular Biology, Biophysics Interdepartmental Group, and Collaborative Program in Neuroscience, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada.
authors.forename: George
authors.identifier: 0000-0002-6114-9947
authors.initials: G
authors.lastname: Harauz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D004676:Myelin Basic Protein / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D017434:Protein Structure, Tertiary; D051076:Proto-Oncogene Proteins c-fyn / Q000737:chemistry*; D013816:Thermodynamics; D014494:Unithiol / Q000737:chemistry; D014867:Water / Q000737:chemistry*; D018909:src Homology Domains
chemical_list: D008051:Lipid Bilayers; D004676:Myelin Basic Protein; D010455:Peptides; D014867:Water; D010767:Phosphorylcholine; D014494:Unithiol; C028810:dodecylphosphocholine; D011392:Proline; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D004134:Dimyristoylphosphatidylcholine
keywords: Fyn-SH3; GROMACS; amphipathic α-helix; intrinsically disordered protein (IDP); molecular dynamics (MD) simulations; molecular recognition fragment (MoRF); myelin basic protein (MBP); poly-proline type II (PPII)