Modeling of serine protease prototype reactions with the flexible effective fragment potential quantum mechanical/molecular mechanical method

Nemukhin, Alexander V.; Grigorenko, Bella L.; Rogov, A. V.; Topol, Igor A.; Burt, Stanley K.

doi:10.1007/s00214-003-0556-x

Cited by 39 publications

(39 citation statements)

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“…Therefore, due to the stabilizing effect of Glu325 on the imidazolium cation, the one proton mechanism is ener getically more favorable. These results are in complete agreement with the results of our previous calculations of the hydrolysis in the active site of acetylcholinesterase, which is similar in the structure and the mechanism of hydrolysis to BuChE, 13 and also with other results of mod eling of the mechanisms of hydrolysis of serine proteases 28 and carboxypeptidases. 10 To sum up, the results of QM/MM simulation showed that the Asp70Gly single mutation of butyrylcholinest erase does not lead to the qualitatively different energy profile of the hydrolysis of succinylcholine for the acyla tion step compared to the native enzyme.…”

Section: Resultssupporting

confidence: 93%

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

et al. 2010

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Section: Resultssupporting

confidence: 93%

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

et al. 2010

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“…Note that theoretical investigations on the first step of the cleavage reaction by subtilisin‐like serine proteases also observed endothermic reaction while overall reaction is exothermic reaction 11, 22, 53. The concerted reactionof the INT formation in furin is extensively supported by theoretical investigations in other serine proteases 11, 22, 53–56…”

Section: Resultsmentioning

confidence: 79%

Combined QM/MM mechanistic study of the acylation process in furin complexed with the H5N1 avian influenza virus hemagglutinin's cleavage site

et al. 2008

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Combined quantum mechanical/molecular mechanical (QM/MM) techniques have been applied to investigate the detailed reaction mechanism of the first step of the acylation process by furin in which the cleavage site of the highly pathogenic avian influenza virus subtype H5N1 (HPH5) acts as its substrate. The energy profile shows a simultaneous mechanism, known as a concerted reaction, of the two subprocesses: the proton transfer from Ser368 to His194 and the nucleophilic attack on the carbonyl carbon of the scissile peptide of the HPH5 cleavage site with a formation of tetrahedral intermediate (INT). The calculated energy barrier for this reaction is 16.2 kcal.mol(-1) at QM/MM B3LYP/6-31+G*//PM3-CHARMM22 level of theory. Once the reaction proceeds, the ordering of the electrostatic stabilization by protein environment is of the enzyme-substrate < transition state < INT complexes. Asp153 was found to play the most important role in the enzymatic reaction by providing the highest degree of intermediate complex stabilization. In addition, the negatively charged carbonyl oxygen of INT is well stabilized by the oxyanion hole constructed by Asn295's carboxamide and Ser368's backbone.

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“…Although reliability of the QM/MM approach applied in this work was tested in many challenging tests27 and used before for successful simulations of the serine protease catalytic cycle28 and for modeling chemical reactions in water,42, 43 its direct application to biological problems still requires certain caution. This methodology is based on the analysis of stationary points on the potential energy surface, but not of the free energy surface.…”

Section: Discussionmentioning

confidence: 99%

“…In the QM subsystem, the energy and forces acting on the atoms are computed according to quantum mechanical equations, while the atoms within the MM subsystem interact between themselves following the classical rules with the selected set of force‐field parameters. The simulations described in this work have been performed by using our QM/MM realization25–28 based on the effective fragment potential theory 29. The essential feature of this flexible effective fragment QM/MM technique is that the coupling of QM and MM subsystems is treated at ab initio level, while all empirical parameters are contained entirely in the MM part.…”

Section: Simulationsmentioning

confidence: 99%

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

et al. 2005

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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.

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Modeling of serine protease prototype reactions with the flexible effective fragment potential quantum mechanical/molecular mechanical method

Cited by 39 publications

References 0 publications

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

Combined QM/MM mechanistic study of the acylation process in furin complexed with the H5N1 avian influenza virus hemagglutinin's cleavage site

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

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