Density functional based parametrization of a valence bond method and its applications in quantum‐classical molecular dynamics simulations of enzymatic reactions

Grochowski, Paweł; Lesyng, Bogdan; Bała, Piotr; McCammon, J. Andrew

doi:10.1002/(sici)1097-461x(1996)60:6<1143::aid-qua4>3.0.co;2-#

Cited by 55 publications

(57 citation statements)

References 35 publications

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“…The potential energy surface is described with a two-state empirical valence bond potential (20,21) based on the GROMOS force field (22), including Morse potentials for the donor-hydride and acceptor-hydride bonds. This potential allows chemical bonds to break and form during the hydride transfer reaction.…”

Section: Methodsmentioning

confidence: 99%

Network of coupled promoting motions in enzyme catalysis

Agarwal

Billeter

Rajagopalan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

447

595

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A network of coupled promoting motions in the enzyme dihydrofolate reductase is identified and characterized. The present identification is based on genomic analysis for sequence conservation, kinetic measurements of multiple mutations, and mixed quantum͞ classical molecular dynamics simulations of hydride transfer. The motions in this network span time scales of femtoseconds to milliseconds and are found on the exterior of the enzyme as well as in the active site. This type of network has broad implications for an expanded role of the protein fold in catalysis as well as ancillaries such as the engineering of altered protein function and the action of drugs distal to the active site.A relationship between the motion of protein structural elements and activity has been implicated in enzyme catalysis (1-3). Evidence for the existence of promoting vibrations or modes that augment catalytic activity has been sought for a number of enzymes. At the amino acid level, motions of residues both in and distal to the active site have been proposed to participate in catalysis. The identification, characterization, and clarification of the function of such proximal and distal promoting motions present a challenging task. Recently the importance of coupled motions sampled in differing time domains involving distal residues in the enzyme dihydrofolate reductase (DHFR; EC 1.5.1.3) has been suggested by a combination of NMR experiments (microsecond to picosecond) (4), classical molecular dynamics simulations (nanosecond) (5), and kinetic experiments for site-directed mutants (millisecond to second) (6, 7). Here we report the results of genomic analysis, kinetic measurements of multiple mutations, and mixed quantum͞classical molecular dynamics simulations (8) of the hydride transfer step in DHFR. Based on the crystal structure framework, these results provide a description of specific residue motions and their linkage to enzyme catalysis.DHFR is required for normal folate metabolism in prokaryotes and eukaryotes. It catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate (THF) by using nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme. Specifically, the pro-R hydride of NADPH is transferred to the C6 of the pterin with concurrent protonation at the N5 position. This reaction is essential to maintain necessary levels of THF needed to support the biosynthesis of purines, pyrimidines, and amino acids, fostering DHFR as a pharmacological target. As a result of its importance, DHFR has been studied extensively with a wide range of methodologies.X-ray crystallographic studies indicate that the Escherichia coli DHFR enzyme contains an eight-stranded ␤-sheet and four ␣-helices interspersed with flexible loop regions that connect these structural elements (ref. 9; see Fig. 1). Depending on the nature of the bound ligand, three different conformations have been observed for a surface loop formed by residues 9-24 (denoted the Met-20 loop). When the DHF substrate and NADPH coenzyme are bound, the Met-20...

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Section: Methodsmentioning

confidence: 99%

Network of coupled promoting motions in enzyme catalysis

Agarwal

Billeter

Rajagopalan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

447

595

View full text Add to dashboard Cite

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“…The evaluation of the AVB Hamiltonian matrix applied in this study differs somewhat from the original method presented in 8 and was developed in order to simplify and systematize the parameterization procedure.…”

Section: Approximate Valence Bond Methodsmentioning

confidence: 99%

“…The second set of quantities calculated in the system (9) are the combination coefficients c c and c i . According to the properties of the AVB method derived in 8, the actual combination coefficients are related to the effective atomic charges of the molecule: where q ca and q ia denote charges of atoms in the covalent and ionic structures, respectively. The coefficients c should be therefore parameterized so that the AVB effective atomic charges reproduce the ESP charges derived from the QM calculations.…”

Section: Approximate Valence Bond Methodsmentioning

confidence: 99%

“…Such a mixed quantum classical approach was applied in this study. The aim was to parameterize, within the approximate valence bond (AVB) formalism 8, the potential energy surface to describe possible paths of the enzymatic reaction catalyzed by the human immunodeficiency virus type 1 protease (HIV‐1 PR). This will permit classical or quantum classical molecular dynamics simulations of this reaction.…”

Section: Introductionmentioning

confidence: 99%

“…An empirical version of the valence bond (VB) method was first proposed by Warshel 9 to describe energy surfaces for enzymatic reactions. The similar AVB approach uses ab initio type of calculations and applies a different parameterization strategy 8. This allows calculating of the Born–Oppenheimer energy surface for the nuclei in an enzyme active site.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Parameterization of the approximate valence bond (AVB) method to describe potential energy surface in the reaction catalyzed by HIV-1 protease

Trylska

Grochowski

Geller

2001

Int. J. Quantum Chem.

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Simulation of slow reaction with quantum character: Neutral hydrolysis of carboxylic ester

Lensink¹,

Mavri²,

Berendsen³

1999

J. Comput. Chem.

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By computer simulation, using both quantum and classical dynamics, we determined the rate constant and the kinetic isotope effect of the rate‐determining step in the neutral hydrolysis of p‐methoxyphenyl dichloroacetate in aqueous solution. This step involves a proton transfer concerted with the formation of a CO bond. A method of biased sampling was used; the Gibbs free energy of the biased configuration from which proton transfer is likely to occur was determined by a combination of semiempirical quantum calculations and thermodynamic integration. The proton dynamics was modeled with the quantum‐dynamical density matrix evolution method that includes nonadiabatic pathways. The proton dynamics is driven by a fluctuating proton potential that was derived from a classical molecular dynamics simulation of the system including solvent. The calculated rate constant of 3×10−2 s−1 agrees within the error of the calculation with the experimentally observed value of 2.78×10−3. The calculated pseudo‐first‐order kinetic isotope effect of 3.9 is in good agreement with the experimentally observed value of 3.2. The results show the feasibility of computational approaches to slow reactions in complex environments, where proton transfer with an essential quantum‐dynamical nature is the rate‐limiting step. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 886–895, 1999

show abstract

Density functional based parametrization of a valence bond method and its applications in quantum‐classical molecular dynamics simulations of enzymatic reactions

Cited by 55 publications

References 35 publications

Network of coupled promoting motions in enzyme catalysis

Network of coupled promoting motions in enzyme catalysis

Parameterization of the approximate valence bond (AVB) method to describe potential energy surface in the reaction catalyzed by HIV-1 protease

Simulation of slow reaction with quantum character: Neutral hydrolysis of carboxylic ester

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