Comparison of computational approaches for predicting the effects of missense mutations on p53 function |
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| Affiliation: | 1. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States;2. IBM Almaden Research Center, San Jose, CA 95120, United States;3. Department of Chemistry, Stanford University, Stanford, CA 94305, United States;1. Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth and Periodontal Regeneration, Kyung Hee University, Seoul, Republic of Korea;2. Department of Conservative Dentistry, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea;3. Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea;1. Department of Metallurgical Engineering, University of Concepción, Concepción, Chile;2. Center for Research in Mathematical Engineering, University of Concepción, Concepción, Chile;3. Department of Mechanical Engineering, University of Concepción, Concepción, Chile;4. Institute of Biocolloid Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine;5. Faculty of Engineering and Geological Sciences, Northern Catholic University, Chile;1. Department of Mechanical and Power Engineering, Nanjing Tech University, Nanjing, Jiangsu Province 210009, China;2. State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, Jiangsu Province 210009, China;3. Department of Mechanical Engineering, Wuhan Institute of Technology, Wuhan, Hubei Province 430070, China |
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| Abstract: | 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. |
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