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

Michel A. Cuendet, Mark Tuckerman

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)3504-3512
Number of pages9
JournalJournal of Chemical Theory and Computation
Volume8
Issue number10
DOIs
StatePublished - Oct 9 2012

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Free energy
free energy
Thermodynamics
perturbation
thermodynamics
Molecules
molecules
energy
sampling
Sampling
Dipeptides
Solvation
alanine
Alanine
solvation
degrees of freedom

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computer Science Applications

Cite this

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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.

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