Open AccessOptimization of Alchemical Pathways Using Extended Thermodynamic Integration
Author(s) -
Anita de Ruiter,
Dražen Petrov,
Chris Oostenbrink
Publication year - 2020
Publication title -
journal of chemical theory and computation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.001
H-Index - 185
eISSN - 1549-9626
pISSN - 1549-9618
DOI - 10.1021/acs.jctc.0c01170
Subject(s) - thermodynamic integration , curvature , smoothness , hamiltonian (control theory) , statistical physics , computer science , physics , energy (signal processing) , mathematics , mathematical optimization , geometry , mathematical analysis , quantum mechanics
Thermodynamic integration (TI) is a commonly used method to determine free-energy differences. One of its disadvantages is that many intermediate λ-states need to be sampled in order to be able to integrate accurately over ⟨∂ H /∂λ⟩. Here, we use the recently introduced extended TI to study alternative parameterizations of H (λ) and its influence on the smoothness of the ⟨∂ H /∂λ⟩ curves as well as the efficiency of the simulations. We find that the extended TI approach can be used to select curves of low curvature. An optimal parameterization is suggested for the calculation of hydration free energies. For calculations of relative binding free energies, we show that optimized parameterizations of the Hamiltonian in the unbound state also effectively lower the curvature in the bound state of the ligand.