Kinetic computational alanine scanning: application to p53 oligomerization.
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.
Chong
Lillian T
LT
Department of Chemistry, Stanford University, Stanford, CA 94305-5447, USA.
Swope
William C
WC
Pitera
Jed W
JW
Pande
Vijay S
VS
D000409:Alanine / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D019281:Dimerization; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D017510:Protein Folding; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D000409:Alanine