Effect of the integration method on the accuracy and computational efficiency of free energy calculations using thermodynamic integration

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Jorge, Miguel and Garrido, Nuno M. and Queimada, Antonio J. and Economou, Ioannis G. and Macedo, Eugenia A. (2010) Effect of the integration method on the accuracy and computational efficiency of free energy calculations using thermodynamic integration. Journal of Chemical Theory and Computation, 6 (4). pp. 1018-1027. ISSN 1549-9618 (https://doi.org/10.1021/ct900661c)

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Abstract

Although calculations of free energy using molecular dynamics simulations have gained significant importance in the chemical and biochemical fields, they still remain quite computationally intensive. Furthermore, when using thermodynamic integration, numerical evaluation of the integral of the Hamiltonian with respect to the coupling parameter may introduce unwanted errors in the free energy. In this paper, we compare the performance of two numerical integration techniques-the trapezoidal and Simpson's rules and propose a new method, based on the analytic integration of physically based fitting functions that are able to accurately describe the behavior of the data. We develop and test our methodology by performing detailed studies on two prototype systems, hydrated methane and hydrated methanol, and treat Lennard-Jones and electrostatic contributions separately. We conclude that the widely used trapezoidal rule may introduce systematic errors in the calculation, but these errors are reduced if Simpson's rule is employed, at least for the electrostatic component. Furthermore, by fitting thermodynamic integration data, we are able to obtain precise free energy estimates using significantly fewer data points (5 intermediate states for the electrostatic component and 11 for the Lennard-Jones term), thus significantly decreasing the associated computational cost. Our method and improved protocol were successfully validated by computing the free energy of more complex systems hydration of 2-methylbutanol and of 4-nitrophenol-thus paving the way for widespread use in solvation free energy calculations of drug molecules.

ORCID iDs

Jorge, Miguel ORCID logoORCID: https://orcid.org/0000-0003-3009-4725, Garrido, Nuno M., Queimada, Antonio J., Economou, Ioannis G. and Macedo, Eugenia A.;
  • Item type:Article
    ID code:42578
    Dates:
    Date
    Event
    April 2010
    Published
    24 February 2010
    Published Online
    Notes:This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/ct900661c.
    Subjects:Technology > Chemical engineering
    Department:Faculty of Engineering > Chemical and Process Engineering
    Depositing user: Pure Administrator
    Date deposited:15 Jan 2013 16:19
    Last modified:11 Nov 2024 10:19
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/42578
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