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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

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
Authors
Issue Date2008
PublisherAmerican Institute of Physics. The Journal's web site is located at http://jcp.aip.org/jcp/staff.jsp
Citation
Journal Of Chemical Physics, 2008, v. 128 n. 3, article no. 034105 How to Cite?
Abstract
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 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.
Persistent Identifierhttp://hdl.handle.net/10722/168272
ISSN
2013 Impact Factor: 3.122
ISI Accession Number ID
References

 

Author Affiliations
  1. Duke University
DC FieldValueLanguage
dc.contributor.authorHu, Hen_US
dc.contributor.authorLu, Zen_US
dc.contributor.authorParks, JMen_US
dc.contributor.authorBurger, SKen_US
dc.contributor.authorYang, Wen_US
dc.date.accessioned2012-10-08T03:16:54Z-
dc.date.available2012-10-08T03:16:54Z-
dc.date.issued2008en_US
dc.identifier.citationJournal Of Chemical Physics, 2008, v. 128 n. 3, article no. 034105en_US
dc.identifier.issn0021-9606en_US
dc.identifier.urihttp://hdl.handle.net/10722/168272-
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.en_US
dc.languageengen_US
dc.publisherAmerican Institute of Physics. The Journal's web site is located at http://jcp.aip.org/jcp/staff.jspen_US
dc.relation.ispartofJournal of Chemical Physicsen_US
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 surfaceen_US
dc.typeArticleen_US
dc.identifier.emailHu, H:haohu@hku.hken_US
dc.identifier.authorityHu, H=rp00707en_US
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1063/1.2816557en_US
dc.identifier.pmid18205486-
dc.identifier.scopuseid_2-s2.0-38349143673en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-38349143673&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume128en_US
dc.identifier.issue3, article no. 034105en_US
dc.identifier.isiWOS:000252471100005-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHu, H=7404097564en_US
dc.identifier.scopusauthoridLu, Z=36708080000en_US
dc.identifier.scopusauthoridParks, JM=10143634800en_US
dc.identifier.scopusauthoridBurger, SK=12144224600en_US
dc.identifier.scopusauthoridYang, W=7407757509en_US
dc.identifier.citeulike9397639-

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