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Molecular dynamics simulations of peptides containing an unnatural amino acid: Dimerization, folding, and protein binding
Author(s) -
Yu Haibo,
Daura Xavier,
van Gunsteren Wilfred F.
Publication year - 2003
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10502
Subject(s) - chemistry , tripeptide , beta sheet , hydrogen bond , molecular dynamics , peptide , amino acid , dimer , steric effects , stereochemistry , folding (dsp implementation) , protein folding , crystallography , computational chemistry , molecule , organic chemistry , biochemistry , electrical engineering , engineering
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 2 CCONH‐2‐MeO‐C 6 H 3 ‐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 1a (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‐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 β‐sheet interactions between proteins. Proteins 2003. © 2003 Wiley‐Liss, Inc.