期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 11, 页码 4961-4966出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914540107
关键词
biophysical simulation; domain motion; free energy; collective variables
资金
- National Science Foundation [DMR-6427643, DMS-0718172, DMS-0708140]
- Office of Naval Research [N00014-04-1-6046]
- TeraGrid [MCB070073N]
We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168-175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t -> r '' transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 angstrom, with a twist of 90 relative to the equatorial domain, and the root-mean-squared deviation relative to the r '' conformer is reduced from 13 to 5 angstrom, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 angstrom from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal/mol for the free-energy barrier between conformers in both cases.
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