### 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 Simpsons 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 Simpsons 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.

Original language | English |
---|---|

Pages (from-to) | 1018-1027 |

Number of pages | 10 |

Journal | Journal of Chemical Theory and Computation |

Volume | 6 |

Issue number | 4 |

DOIs | |

Publication status | Published - 13 Apr 2010 |

Externally published | Yes |

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### ASJC Scopus subject areas

- Computer Science Applications
- Physical and Theoretical Chemistry

### Cite this

*Journal of Chemical Theory and Computation*,

*6*(4), 1018-1027. https://doi.org/10.1021/ct900661c

**Effect of the integration method on the accuracy and computational efficiency of free energy calculations using thermodynamic integration.** / Jorge, Miguel; Garrido, Nuno M.; Queimada, António J.; Economou, Ioannis; MacEdo, Eugénia A.

Research output: Contribution to journal › Article

*Journal of Chemical Theory and Computation*, vol. 6, no. 4, pp. 1018-1027. https://doi.org/10.1021/ct900661c

}

TY - JOUR

T1 - Effect of the integration method on the accuracy and computational efficiency of free energy calculations using thermodynamic integration

AU - Jorge, Miguel

AU - Garrido, Nuno M.

AU - Queimada, António J.

AU - Economou, Ioannis

AU - MacEdo, Eugénia A.

PY - 2010/4/13

Y1 - 2010/4/13

N2 - 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 Simpsons 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 Simpsons 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.

AB - 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 Simpsons 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 Simpsons 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.

UR - http://www.scopus.com/inward/record.url?scp=77951141262&partnerID=8YFLogxK

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U2 - 10.1021/ct900661c

DO - 10.1021/ct900661c

M3 - Article

VL - 6

SP - 1018

EP - 1027

JO - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

SN - 1549-9618

IS - 4

ER -