Journal article
Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics
Proceedings of the National Academy of Sciences - PNAS, v 107(11), pp 4961-4966
16 Mar 2010
PMID: 20194785
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics
- Creators
- Cameron F Abrams - Department of Chemical and Biological Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. cfa22@drexel.eduEric Vanden-Eijnden
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 107(11), pp 4961-4966
- Publisher
- PNAS; United States
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000275714300031
- Scopus ID
- 2-s2.0-77950448255
- Other Identifier
- 991014877689304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology