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Exploring Chemical Reactivity in Enzyme Catalyzed Processes Using QM/MM Methods: An Application to Dihydrofolate Reductase

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Quantum Modeling of Complex Molecular Systems

Part of the book series: Challenges and Advances in Computational Chemistry and Physics ((COCH,volume 21))

Abstract

Enzymes are the catalysts used by living organisms to accelerate chemical processes under physiological conditions. In this chapter, we illustrate the current view about the origin of their extraordinary rate enhancement based on molecular simulations and, in particular, on methods based on the combination of Quantum Mechanics and Molecular Mechanics potentials which provide a solution to treat the chemical reactivity of these large and complex molecular systems. Computational studies on Dihydrofolate Reductase have been selected as a conductor wire to present the evolution and difficulties to model chemical reactivity in enzymes. The results discussed here show that experimental observations can be currently understood within the framework of Transition State Theory provided that the adequate simulations are carried out. Protein dynamics, quantum tunnelling effects and conformational diversity are essential ingredients to explain the complex behaviour of these amazing molecular machineries.

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Abbreviations

2D-PMF:

Two dimensional potential of mean force

AM1:

Austin model 1

AM1-SRP:

Austin model 1—specific reaction parameters

BsDHFR:

Geobacillus stearothermophilus Dihydrofolate Reductase

DAD:

Donor acceptor distance

DFT:

Density futctional Theory

DHF:

7,8-dihydrofolate

DHFR:

Dihydrofolate Reductase

EA-VTST:

Ensemble-averaged variational transition state theory

EcDHFR:

Escherichia Coli Dihydrofolate Reductase

Eelec :

Electronic energy

EVB:

Empirical valence bond

FEP:

Free energy perturbation

GHO:

Generalized hybrid orbital

IRC:

Intrinsic reaction coordinate

KIE:

Kinetic isotope effect

LDH:

Lactate Dihydrogenase

LSCF:

Local self-consistent field

MD:

Molecular dynamics

MM:

Molecular mechanics

NADPH:

Nicotinamide adenine dinucleotide phosphate

PES:

Potential energy surface

PM3:

Parameterized model 3

PMF:

Potential of mean force

PS:

Product state

QM:

Quantum mechanics

QM-FEP:

Quantum mechanics free energy perturbation

QM/MM:

Quantum mechanical/molecular mechanics

RS:

Reactant state

THF:

5,6,7,8-tetrahydrofolate

TS:

Transition state

TST:

Transition state theory

V:

Potential energy

Vnn :

Nuclear repulsion energy

WHAM:

Weighted histogram analysis method

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Acknowledgements

This work was supported by the Spanish Ministerio de Economía y Competitividad for project CTQ2012-36253-C03, Universitat Jaume I (project P1 1B2014-26) and Generalitat Valenciana (PROMETEOII/2014/022).

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Authors and Affiliations

  1. Departament de Química Física i Analítica, Universitat Jaume I, 12071, Castelló, Spain

    J. Javier Ruiz-Pernía & Vicent Moliner

  2. Departament de Química Física, Universitat de València, 46100, Burjasot, Spain

    Iñaki Tuñón

Authors
  1. J. Javier Ruiz-Pernía
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  2. Vicent Moliner
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  3. Iñaki Tuñón
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Corresponding authors

Correspondence to Vicent Moliner or Iñaki Tuñón .

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Editors and Affiliations

  1. UMR 7565—SRSMC, Université de Lorraine, Nancy-Vandoeuvre, France

    Jean-Louis Rivail

  2. UMR 7565—SRSMC, Université de Lorraine, Nancy-Vandoeuvre, France

    Manuel Ruiz-Lopez

  3. UMR 7565—SRSMC, Université de Lorraine, Nancy-Vandoeuvre, France

    Xavier Assfeld

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Javier Ruiz-Pernía, J., Moliner, V., Tuñón, I. (2015). Exploring Chemical Reactivity in Enzyme Catalyzed Processes Using QM/MM Methods: An Application to Dihydrofolate Reductase. In: Rivail, JL., Ruiz-Lopez, M., Assfeld, X. (eds) Quantum Modeling of Complex Molecular Systems. Challenges and Advances in Computational Chemistry and Physics, vol 21. Springer, Cham. https://doi.org/10.1007/978-3-319-21626-3_15

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