title: Stability of the beta-sheet of the WW domain: A molecular dynamics simulation study.
abstract: The WW domain consists of approximately 40 residues, has no disulfide bridges, and forms a three-stranded antiparallel beta-sheet that is monomeric in solution. It thus provides a model system for studying beta-sheet stability in native proteins. We performed molecular dynamics simulations of two WW domains, YAP65 and FBP28, with very different stability characteristics, in order to explore the initial unfolding of the beta-sheet. The less stable YAP domain is much more sensitive to simulation conditions than the FBP domain. Under standard simulation conditions in water (with or without charge-balancing counterions) at 300 K, the beta-sheet of the YAP WW domain disintegrated at early stages of the simulations. Disintegration commenced with the breakage of a hydrogen bond between the second and third strands of the beta-sheet due to an anticorrelated transition of the Tyr-28 psi and Phe-29 phi angles. Electrostatic interactions play a role in this event, and the YAP WW domain structure is more stable when simulated with a complete explicit model of the surrounding ionic strength. Other factors affecting stability of the beta-sheet are side-chain packing, the conformational entropy of the flexible chain termini, and the binding of cognate peptide.
authors.affiliation: European Molecular Biology Laboratory, 69012 Heidelberg, Germany.
authors.forename: G T
authors.initials: GT
authors.lastname: Ibragimova
authors.forename: R C
authors.initials: RC
authors.lastname: Wade
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018797:Cell Cycle Proteins; D003198:Computer Simulation; D050556:Fatty Acid-Binding Proteins; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics; D014157:Transcription Factors; D014867:Water / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050556:Fatty Acid-Binding Proteins; C106410:Fnbp1 protein, mouse; D008024:Ligands; D010446:Peptide Fragments; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D014867:Water