Comparison of computational approaches for predicting the effects of missense mutations on p53 function.
We applied our recently developed kinetic computational mutagenesis (KCM) approach [L.T. Chong, W.C. Swope, J.W. Pitera, V.S. Pande, Kinetic computational alanine scanning: application to p53 oligomerization, J. Mol. Biol. 357 (3) (2006) 1039-1049] along with the MM-GBSA approach [J. Srinivasan, T.E. Cheatham 3rd, P. Cieplak, P.A. Kollman, D.A. Case, Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices, J. Am. Chem. Soc. 120 (37) (1998) 9401-9409; P.A. Kollman, I. Massova, C.M. Reyes, B. Kuhn, S. Huo, L.T. Chong, M. Lee, T. Lee, Y. Duan, W. Wang, O. Donini, P. Cieplak, J. Srinivasan, D.A. Case, T.E. Cheatham 3rd., Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models, Acc. Chem. Res. 33 (12) (2000) 889-897] to evaluate the effects of all possible missense mutations on dimerization of the oligomerization domain (residues 326-355) of tumor suppressor p53. The true positive and true negative rates for KCM are comparable (within 5%) to those of MM-GBSA, although MM-GBSA is much less computationally intensive when it is applied to a single energy-minimized configuration per mutant dimer. The potential advantage of KCM is that it can be used to directly examine the kinetic effects of mutations.
Chong
Lillian T
LT
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. ltchong@pitt.edu
Pitera
Jed W
JW
Swope
William C
WC
Pande
Vijay S
VS
D019295:Computational Biology; D003198:Computer Simulation; D006801:Humans; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics* / Q000502:physiology; D017510:Protein Folding; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*
D016159:Tumor Suppressor Protein p53