EXTENSIVE MOLECULAR DYNAMICS SIMULATIONS OF A BETA-HAIRPIN-FORMING PEPTIDE

摘要

Molecular dynamics simulations of the water-solvated, beta-hairpin-forming linear peptide Y-Q-N-P-D-G-S-Q-A (one-letter amino acid code) [F. J. Blanco et al. (1993) J. Am. Chem. Sec. 115, 5887-5888] were performed at simulation temperatures of 278 K and 270 K. At 278 K, the overall beta-hairpin state remained stable for approximately 2.06 ns, after which it underwent an unfolding transition to a more disordered, random coil-like state that was maintained for the remainder of the 3.50-ns simulation. A comparison of experimental H-alpha-C-alpha order parameters determined at 278 K with order parameters derived from the simulation revealed that the beta-hairpin state is consistent with the experimental results, whereas the random coil-like state yields order parameters that are all much lower than the experimental values. This indicates that the random coil-like state is not highly populated in the experimental system. An examination of the dynamic behavior of the simulated peptide/solvent system indicated that a lower temperature may yield a more stable trajectory. At 270 K, the beta-hairpin conformation remained stable for approximately 2.32 ns, after which the peptide again unfolded and maintained a less-ordered state for the remainder of the 3.50-ns simulation. The less-ordered state observed at 270 K is more compact than the disordered state observed at 278 K; the former may represent a folding intermediate. The folded state is stabilized primarily by a number of transient hydrogen bonding interactions, including hydrogen bonds between Tyr-1 O and Ala-9 HN, between Asn-3 HN and Ser-7 O, and between the side chain of Asn-3 and backbone groups of Asp-5, Gly-6, and Ser-7. The 270 K simulation was restarted at 2.10 ns, with a single loose nuclear Overhauser effect (NOE) upper-bound distance restraint of 5.5 Angstrom added between Gln-2 H-alpha and Gln-8 H-alpha. This single restraint maintained folded conformations for the remaining 10.50 ns of the trajectory. The restraint was frequently violated (i.e., the restraint potential frequently took on nonzero values) during the period between about 0.24 and 6.51 ns of the restrained trajectory. Between about 6.51 and 8.04 ns of the restrained trajectory, the restraint remained well-satisfied, demonstrating a transiently stable, alternate-folded conformational state during this period. These results indicate that even long (by today's standards), similar to 1 ns timescale trajectories may not always be sufficient to prove the long-term stability of the native state in simulations of biomolecules, and that apparently converged states may only be metastable. (C) 1996 John Wiley & Sons, Inc. [References: 77]