Kinetic Computational Alanine Scanning: Application to p53 Oligomerization

L.T. Chong, W. C. Swope, J. W. Pitera, and V. S. Pande.
Journal of Molecular Biology (2006)

SUMMARY: Roughly half of all known cancers involve a mutation in a single protein: p53. P53 serves to protect us from getting cancer; when p53 fails, one often gets cancer. We have developed a new method for predicting how mutations in p53, a protein central to cancer, would impact p53. This new method is naturally suited for distributed computing and can predict several mutations found to date.

ABSTRACT: We have developed a novel computational alanine scanning approach that involves analysis of ensemble unfolding kinetics at high temperature to identify residues that are critical for the stability of a given protein. This approach has been applied to dimerization of the oligomerization domain (residues 326-355) of tumor suppressor p53. As validated by experimental results, our approach has reasonable success in identifying deleterious mutations, including mutations that have been linked to cancer. We discuss a method for determining the effect of mutations on the location of the dimerization transition state.

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