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Quantum mechanics/molecular mechanics minimum free-energy path for accurate reaction energetics in solution and enzymes: sequential sampling and optimization on the potential of mean force surface.

Publication ,  Journal Article
Hu, H; Lu, Z; Parks, JM; Burger, SK; Yang, W
Published in: The Journal of chemical physics
January 2008

To accurately determine the reaction path and its energetics for enzymatic and solution-phase reactions, we present a sequential sampling and optimization approach that greatly enhances the efficiency of the ab initio quantum mechanics/molecular mechanics minimum free-energy path (QM/MM-MFEP) method. In the QM/MM-MFEP method, the thermodynamics of a complex reaction system is described by the potential of mean force (PMF) surface of the quantum mechanical (QM) subsystem with a small number of degrees of freedom, somewhat like describing a reaction process in the gas phase. The main computational cost of the QM/MM-MFEP method comes from the statistical sampling of conformations of the molecular mechanical (MM) subsystem required for the calculation of the QM PMF and its gradient. In our new sequential sampling and optimization approach, we aim to reduce the amount of MM sampling while still retaining the accuracy of the results by first carrying out MM phase-space sampling and then optimizing the QM subsystem in the fixed-size ensemble of MM conformations. The resulting QM optimized structures are then used to obtain more accurate sampling of the MM subsystem. This process of sequential MM sampling and QM optimization is iterated until convergence. The use of a fixed-size, finite MM conformational ensemble enables the precise evaluation of the QM potential of mean force and its gradient within the ensemble, thus circumventing the challenges associated with statistical averaging and significantly speeding up the convergence of the optimization process. To further improve the accuracy of the QM/MM-MFEP method, the reaction path potential method developed by Lu and Yang [Z. Lu and W. Yang, J. Chem. Phys. 121, 89 (2004)] is employed to describe the QM/MM electrostatic interactions in an approximate yet accurate way with a computational cost that is comparable to classical MM simulations. The new method was successfully applied to two example reaction processes, the classical SN2 reaction of Cl-+CH3Cl in solution and the second proton transfer step of the reaction catalyzed by the enzyme 4-oxalocrotonate tautomerase. The activation free energies calculated with this new sequential sampling and optimization approach to the QM/MM-MFEP method agree well with results from other simulation approaches such as the umbrella sampling technique with direct QM/MM dynamics sampling, demonstrating the accuracy of the iterative QM/MM-MFEP method.

Duke Scholars

Published In

The Journal of chemical physics

DOI

EISSN

1089-7690

ISSN

0021-9606

Publication Date

January 2008

Volume

128

Issue

3

Start / End Page

034105

Related Subject Headings

  • Thermodynamics
  • Static Electricity
  • Software
  • Quantum Theory
  • Molecular Structure
  • Molecular Conformation
  • Models, Theoretical
  • Models, Statistical
  • Models, Molecular
  • Equipment Design
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hu, H., Lu, Z., Parks, J. M., Burger, S. K., & Yang, W. (2008). Quantum mechanics/molecular mechanics minimum free-energy path for accurate reaction energetics in solution and enzymes: sequential sampling and optimization on the potential of mean force surface. The Journal of Chemical Physics, 128(3), 034105. https://doi.org/10.1063/1.2816557
Hu, Hao, Zhenyu Lu, Jerry M. Parks, Steven K. Burger, and Weitao Yang. “Quantum mechanics/molecular mechanics minimum free-energy path for accurate reaction energetics in solution and enzymes: sequential sampling and optimization on the potential of mean force surface.The Journal of Chemical Physics 128, no. 3 (January 2008): 034105. https://doi.org/10.1063/1.2816557.

Published In

The Journal of chemical physics

DOI

EISSN

1089-7690

ISSN

0021-9606

Publication Date

January 2008

Volume

128

Issue

3

Start / End Page

034105

Related Subject Headings

  • Thermodynamics
  • Static Electricity
  • Software
  • Quantum Theory
  • Molecular Structure
  • Molecular Conformation
  • Models, Theoretical
  • Models, Statistical
  • Models, Molecular
  • Equipment Design