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Article: 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
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TitleQuantum 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
 
AuthorsHu, H1
Lu, Z1
Parks, JM1
Burger, SK1
Yang, W1
 
Issue Date2008
 
PublisherAmerican Institute of Physics. The Journal's web site is located at http://jcp.aip.org/jcp/staff.jsp
 
CitationJournal Of Chemical Physics, 2008, v. 128 n. 3, article no. 034105 [How to Cite?]
DOI: http://dx.doi.org/10.1063/1.2816557
 
AbstractTo 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 SN 2 reaction of Cl- + CH3 Cl 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. © 2008 American Institute of Physics.
 
ISSN0021-9606
2013 Impact Factor: 3.122
 
DOIhttp://dx.doi.org/10.1063/1.2816557
 
ISI Accession Number IDWOS:000252471100005
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorHu, H
 
dc.contributor.authorLu, Z
 
dc.contributor.authorParks, JM
 
dc.contributor.authorBurger, SK
 
dc.contributor.authorYang, W
 
dc.date.accessioned2012-10-08T03:16:54Z
 
dc.date.available2012-10-08T03:16:54Z
 
dc.date.issued2008
 
dc.description.abstractTo 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 SN 2 reaction of Cl- + CH3 Cl 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. © 2008 American Institute of Physics.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationJournal Of Chemical Physics, 2008, v. 128 n. 3, article no. 034105 [How to Cite?]
DOI: http://dx.doi.org/10.1063/1.2816557
 
dc.identifier.citeulike9397639
 
dc.identifier.doihttp://dx.doi.org/10.1063/1.2816557
 
dc.identifier.isiWOS:000252471100005
 
dc.identifier.issn0021-9606
2013 Impact Factor: 3.122
 
dc.identifier.issue3, article no. 034105
 
dc.identifier.pmid18205486
 
dc.identifier.scopuseid_2-s2.0-38349143673
 
dc.identifier.urihttp://hdl.handle.net/10722/168272
 
dc.identifier.volume128
 
dc.languageeng
 
dc.publisherAmerican Institute of Physics. The Journal's web site is located at http://jcp.aip.org/jcp/staff.jsp
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Chemical Physics
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.rightsCopyright (2008) American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in (Journal Of Chemical Physics, 2008, v. 128 n. 3, article no. 034105) and may be found at (http://jcp.aip.org/resource/1/jcpsa6/v128/i3/p034105_s1).
 
dc.titleQuantum 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
 
dc.typeArticle
 
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Author Affiliations
  1. Duke University