Lillian T. Chong, Christopher D. Snow, Young Min Rhee, and Vijay S. Pande. Journal of Molecular Biology (2005)
SUMMARY: Roughly half of all known cancers result from mutations in p53. Our first work in the cancer area examines the tetramerization domain of p53. We predict how p53 folds and in doing so, we can predict which amino acid mutations would be relevant. When compared with experiments, our predictions have appeared to agree with experiment and give a new interpretation to existing data.
TECHNICAL ABSTRACT: Dimerization of the p53 oligomerization domain involves coupled folding and binding of monomers. To examine the dimerization, we have performed molecular dynamics (MD) simulations of dimer folding from the rate-limiting transition state ensemble (TSE). Among 799 putative transition state structures that were selected from a large ensemble of high-temperature unfolding trajectories, 129 were identified as members of the TSE via calculation of a 50% transmission coefficient from at least 20 room-temperature simulations. This study is the first to examine the refolding of a protein dimer using MD simulations in explicit water, revealing a folding nucleus for dimerization. Our atomistic simulations are consistent with experiment and offer insight that was previously unobtainable.