QM/MM modeling the Ras–GAP catalyzed hydrolysis of guanosine triphosphate

Citations Over TimeTop 10% of 2005 papers

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.

Related Papers

• → Bipolar hemicyanine cationic probe for simultaneous sensing of ATP and GTP(2023)3 cited
• → Guanosine 5′-triphosphate inhibits growth and stimulates differentiated functions in B16 melanoma cells(1978)16 cited
• → Nucleotide-dependent bisANS binding to tubulin(1999)10 cited
• → Receptor‐stimulated guanine‐nucleotide‐triphosphate binding to guanine‐nucleotide‐binding regulatory proteins(1994)26 cited
• → A Genetically Encoded Fluorescent Sensor Enables Real-time Detection of the Intracellular GTP:GDP Ratio(2019)1 cited