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QM/MM modeling the Ras–GAP catalyzed hydrolysis of guanosine triphosphate
Author(s) -
Grigorenko Bella L.,
Nemukhin Alexander V.,
Topol Igor A.,
Cachau Raul E.,
Burt Stanley K.
Publication year - 2005
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.20472
Subject(s) - gtp' , guanosine diphosphate , guanosine , guanosine triphosphate , chemistry , lytic cycle , ab initio , molecule , reactivity (psychology) , catalysis , transition state , hydrolysis , computational chemistry , chemical physics , crystallography , enzyme , biochemistry , organic chemistry , biology , medicine , alternative medicine , pathology , virus , virology
The mechanism of the hydrolysis reaction of guanosine triphosphate (GTP) by the protein complex Ras–GAP (p21 ras – p120 GAP ) has been modeled by the quantum mechanical—molecular mechanical (QM/MM) and ab initio quantum calculations. Initial geometry configurations have been prompted by atomic coordinates of a structural analog (PDBID:1WQ1). It is shown that the minimum energy reaction path is consistent with an assumption of two‐step chemical transformations. At the first stage, a unified motion of Arg789 of GAP, Gln61, Thr35 of Ras, and the lytic water molecule 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 transition state TS1. At the second stage, Gln61 abstracts and releases protons within the subsystem including Gln61, the lytic water molecule and the γ‐phosphate group of GTP through the corresponding transition state TS2. Direct quantum calculations show that, in this particular environment, the reaction GTP + H 2 O → GDP + H 2 PO 4 −can proceed with reasonable activation barriers of less than 15 kcal/mol at every stage. This conclusion leads to a better understanding of the anticatalytic effect of cancer‐causing mutations of Ras, which has been debated in recent years. Proteins 2005. © 2005 Wiley‐Liss, Inc.