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Mechanisms of guanosine triphosphate hydrolysis by Ras and Ras‐GAP proteins as rationalized by ab initio QM/MM simulations
Author(s) -
Grigorenko Bella L.,
Nemukhin Alexander V.,
Shadrina Maria S.,
Topol Igor A.,
Burt Stanley K.
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21228
Subject(s) - chemistry , ab initio , gtp' , guanosine triphosphate , guanosine , energy landscape , molecule , potential energy surface , transition state , hydrogen bond , crystallography , computational chemistry , chemical physics , enzyme , organic chemistry , catalysis , biochemistry
Abstract The hydrolysis reaction of guanosine triphosphate (GTP) by p21 ras (Ras) has been modeled by using the ab initio type quantum mechanical–molecular mechanical simulations. Initial geometry configurations have been prompted by atomic coordinates of the crystal structure (PDBID: 1QRA) corresponding to the prehydrolysis state of Ras in complex with GTP. Multiple searches of minimum energy geometry configurations consistent with the hydrogen bond networks have been performed, resulting in a series of stationary points on the potential energy surface for reaction intermediates and transition states. It is shown that the minimum energy reaction path is consistent with an assumption of a two‐step mechanism of GTP hydrolysis. At the first stage, a unified action of the nearest residues of Ras and the nearest water molecules results in a substantial spatial separation of the γ‐phosphate group of GTP from the rest of the molecule (GDP). This phase of hydrolysis process proceeds through the low barrier (16.7 kcal/mol) transition state TS1. At the second stage, the inorganic phosphate is formed in consequence of proton transfers mediated by two water molecules and assisted by the Gln61 residue from Ras. The highest transition state at this segment, TS3, is estimated to have an energy 7.5 kcal/mol above the enzyme–substrate complex. The results of simulations are compared to the previous findings for the GTP hydrolysis in the Ras‐GAP (p21 ras –p120 GAP ) protein complex. Conclusions of the modeling lead to a better understanding of the anticatalytic effect of cancer causing mutation of Gln61 from Ras, which has been debated in recent years. Proteins 2007. © 2006 Wiley‐Liss, Inc.