Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics.
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 A, with a twist of 90 degrees relative to the equatorial domain, and the root-mean-squared deviation relative to the r('') conformer is reduced from 13 to 5 A, 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 A 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.
Abrams
Cameron F
CF
Department of Chemical and Biological Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. cfa22@drexel.edu
Vanden-Eijnden
Eric
E
D018834:Chaperonin 60 / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D013696:Temperature
D018834:Chaperonin 60; D015699:HIV Envelope Protein gp120; D021122:Protein Subunits; C514793:gp120 protein, Human immunodeficiency virus 1