### Abstract

Alchemical free energy simulations are commonly used to calculate relative binding or solvation free energies in molecular systems. The convergence of alchemical free energy calculations is often hampered by inefficient sampling of the conformational degrees of freedom, which remain trapped in metastable substates. Here, we show that thermodynamic integration (TI) or free energy perturbation (FEP) can be combined with the recent driven adiabatic free energy dynamics (dAFED) method, in order to enhance conformational sampling along a set of chosen collective variables. The resulting TI-dAFED or FEP-dAFED methods are validated on a two-dimensional analytical problem. The ability of these methods to provide accurate free energy differences for realistic molecular systems is demonstrated by calculating the enantiomerization free energy of the alanine dipeptide in explicit solvent.

Original language | English (US) |
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Pages (from-to) | 3504-3512 |

Number of pages | 9 |

Journal | Journal of Chemical Theory and Computation |

Volume | 8 |

Issue number | 10 |

DOIs | |

State | Published - Oct 9 2012 |

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### ASJC Scopus subject areas

- Physical and Theoretical Chemistry
- Computer Science Applications

### Cite this

**Alchemical free energy differences in flexible molecules from thermodynamic integration or free energy perturbation combined with driven adiabatic dynamics.** / Cuendet, Michel A.; Tuckerman, Mark.

Research output: Contribution to journal › Article

*Journal of Chemical Theory and Computation*, vol. 8, no. 10, pp. 3504-3512. https://doi.org/10.1021/ct300090z

}

TY - JOUR

T1 - Alchemical free energy differences in flexible molecules from thermodynamic integration or free energy perturbation combined with driven adiabatic dynamics

AU - Cuendet, Michel A.

AU - Tuckerman, Mark

PY - 2012/10/9

Y1 - 2012/10/9

N2 - Alchemical free energy simulations are commonly used to calculate relative binding or solvation free energies in molecular systems. The convergence of alchemical free energy calculations is often hampered by inefficient sampling of the conformational degrees of freedom, which remain trapped in metastable substates. Here, we show that thermodynamic integration (TI) or free energy perturbation (FEP) can be combined with the recent driven adiabatic free energy dynamics (dAFED) method, in order to enhance conformational sampling along a set of chosen collective variables. The resulting TI-dAFED or FEP-dAFED methods are validated on a two-dimensional analytical problem. The ability of these methods to provide accurate free energy differences for realistic molecular systems is demonstrated by calculating the enantiomerization free energy of the alanine dipeptide in explicit solvent.

AB - Alchemical free energy simulations are commonly used to calculate relative binding or solvation free energies in molecular systems. The convergence of alchemical free energy calculations is often hampered by inefficient sampling of the conformational degrees of freedom, which remain trapped in metastable substates. Here, we show that thermodynamic integration (TI) or free energy perturbation (FEP) can be combined with the recent driven adiabatic free energy dynamics (dAFED) method, in order to enhance conformational sampling along a set of chosen collective variables. The resulting TI-dAFED or FEP-dAFED methods are validated on a two-dimensional analytical problem. The ability of these methods to provide accurate free energy differences for realistic molecular systems is demonstrated by calculating the enantiomerization free energy of the alanine dipeptide in explicit solvent.

UR - http://www.scopus.com/inward/record.url?scp=84867366593&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867366593&partnerID=8YFLogxK

U2 - 10.1021/ct300090z

DO - 10.1021/ct300090z

M3 - Article

AN - SCOPUS:84867366593

VL - 8

SP - 3504

EP - 3512

JO - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

SN - 1549-9618

IS - 10

ER -