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Computer Simulations of Peptides from the p53 DNA Binding Domain

  1. Author:
    Khalili, M.
    Wales, D. J.

  2. Author Address

    Wales, David J.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Khalili, Mey] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Khalili, Mey] Mitre Corp, Mclean, VA 22102 USA.
    1. Year: 2009
  2. Journal: Journal of Chemical Theory and Computation
    1. 5
    2. 5
    3. Pages: 1380-1392
  4. Type of Article: Article
  1. Abstract:

    We have studied the dynamics and thermodynamics of two of the four evolutionarily conserved segments from the p53 DNA binding domain, using molecular dynamics and replica exchange simulations. These two regions contain well-defined elements of secondary structure (a beta hairpin for region II and an alpha helix for region V) and bind to DNA in the intact protein. They are also mutational hot spots. The goal of our study was to determine the stability and folding propensity of these peptides in isolation. We used three force fields and solvent models (CHARMM19 with EEF1, CHARMM27 with GBMV, GROMOS96 with SPC). The predicted stability, folding propensity, and secondary structures depend upon the potential. Secondary structure predictors identify helical propensity for region II, in agreement with one of the force fields (CHARMM/GBMV). However, the other two potentials favor beta structure for this peptide, although the conformations may differ from the crystal. For region V secondary structure predictions are unclear. Only one force field (CHARMM/GBMV) produces low-lying free energy minima that retain some of the alpha helical structure from the crystal structure. The other two potentials appear to favor beta structure for this peptide.

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  2. DOI: 10.1021/ct8005387
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