Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical-Molecular Mechanical Simulations of Proton Transfer in DNA

Susanta Das, Kwangho Nam, Dan Thomas Major

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

In recent years, a number of quantum mechanical-molecular mechanical (QM/MM) enzyme studies have investigated the dependence of reaction energetics on the size of the QM region using energy and free energy calculations. In this study, we revisit the question of QM region size dependence in QM/MM simulations within the context of energy and free energy calculations using a proton transfer in a DNA base pair as a test case. In the simulations, the QM region was treated with a dispersion-corrected AM1/d-PhoT Hamiltonian, which was developed to accurately describe phosphoryl and proton transfer reactions, in conjunction with an electrostatic embedding scheme using the particle-mesh Ewald summation method. With this rigorous QM/MM potential, we performed rather extensive QM/MM sampling, and found that the free energy reaction profiles converge rapidly with respect to the QM region size within ca. ±1 kcal/mol. This finding suggests that the strategy of QM/MM simulations with reasonably sized and selected QM regions, which has been employed for over four decades, is a valid approach for modeling complex biomolecular systems. We point to possible causes for the sensitivity of the energy and free energy calculations to the size of the QM region, and potential implications.

Original languageEnglish
Pages (from-to)1695-1705
Number of pages11
JournalJournal of Chemical Theory and Computation
Volume14
Issue number3
DOIs
StatePublished - 13 Mar 2018

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.

Funding

*E-mail: [email protected]. ORCID Kwangho Nam: 0000-0003-0723-7839 Dan Thomas Major: 0000-0002-9231-0676 Funding This work has been supported by the Israel Science Foundation (Grant 2146/15 to D.T.M.), the Swedish Research Council (VR 2015-04114 to K.N.), and the University of Texas at Arlington (K.N.).

FundersFunder number
University of Texas at Arlington
Israel Science Foundation2146/15
VetenskapsrådetVR 2015-04114

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