title: Molecular dynamics simulations of peptides containing an unnatural amino acid: dimerization, folding, and protein binding.
abstract: We have performed molecular dynamics (MD) simulations to study the dimerization, folding, and binding to a protein of peptides containing an unnatural amino acid. NMR studies have shown that the substitution of one residue in a tripeptide beta-strand by the unnatural amino acid Hao (5-HO2CCONH-2-MeO-C6H3-CO-NHNH2) modifies the conformational flexibility of the beta-strand and the hydrogen-bonding properties of its two edges: The number of hydrogen-bond donors and acceptors increases at one edge, whereas at the other, they are sterically hindered. In simulations in chloroform, the Hao-containing peptide 9 (i-PrCO-Phe-Hao-Val-NHBu) forms a beta-sheet-like hydrogen-bonded dimer, in good agreement with the available experimental data. Addition of methanol to the solution induces instability of this beta-sheet, as confirmed by the experiments. MD simulations also reproduce the folding of the synthetic peptide 1a (i-PrCO-Hao-Ut-Phe-Ile-Leu-NHMe) into a beta-hairpin-like structure in chloroform. Finally, the Hao-containing peptide, Ac-Ala-Hao-Ala-NHMe, is shown to form a stable complex with the Ras analogue, Rap1 A, in water at room temperature. Together with the available experimental data, these simulation studies indicate that Hao-containing peptides may serve as inhibitors of beta-sheet interactions between proteins.
authors.affiliation: Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zurich, ETH Hönggerberg, 8093 Zürich, Switzerland.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
authors.forename: Xavier
authors.initials: X
authors.lastname: Daura
authors.forename: Wilfred F
authors.initials: WF
authors.lastname: van Gunsteren
mesh_terms: D024322:Amino Acids, Aromatic / Q000737:chemistry*; D003198:Computer Simulation; D019281:Dimerization; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D020827:rap1 GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D024322:Amino Acids, Aromatic; D009842:Oligopeptides; C482443:acetyl-alanyl-alpha-(3-hydrazinocarbonyl-4-methoxyanilino)-alpha-oxoacetyl-alanine methylamide; C482441:alpha-(3-hydrazinocarbonyl-4-methoxyanilino)-alpha-oxoacetic acid; C482442:isopropylcarbonyl-alpha-(3-hydrazinocarbonyl-4-methoxyanilino)-alpha-oxoacetyl-2,5-diaza-2-(2-cyanoethyl)-5-phenylvaleryl-phenylalanyl-isoleucyl-leucine methylamide; D020827:rap1 GTP-Binding Proteins