Molecular Dynamics Simulations of Peptides Containing an Unnatural Amino Acid: Dimerization, Folding, and Protein Binding

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 β-strand by the unnatural amino acid Hao (5-HO 2CCONH-2-MeO-C6H3-CO-NHNH2) modifies the conformational flexibility of the β-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 β-sheet-like hydrogen-bonded dimer, in good agreement with the available experimental data. Addition of methanol to the solution induces instability of this β-sheet, as confirmed by the experiments. MD simulations also reproduce the folding of the synthetic peptide la (i-PrCO-Hao-Ut-Phe-Ile-Leu-NHMe) into a β-hairpin-like structure in chloroform. Finally, the Hao-containing peptide, Ac-Ala-Hao-Ala-N-HMe, 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 β-sheet interactions between proteins. © 2003 Wiley-Liss, Inc.