title: QM/MM modeling the Ras-GAP catalyzed hydrolysis of guanosine triphosphate.
abstract: 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 gamma-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 gamma-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.
authors.affiliation: Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.
authors.forename: Bella L
authors.initials: BL
authors.lastname: Grigorenko
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Nemukhin
authors.forename: Igor A
authors.initials: IA
authors.lastname: Topol
authors.forename: Raul E
authors.initials: RE
authors.lastname: Cachau
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Burt
mesh_terms: D002384:Catalysis; D019295:Computational Biology / Q000379:methods*; D011905:Genes, ras; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D040901:Proteomics / Q000379:methods*; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water; D018631:ras Proteins / Q000737:chemistry*
chemical_list: D046911:Macromolecular Substances; D014867:Water; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D010100:Oxygen