Computing Relative Free Energies of Solvation Using Single Reference Thermodynamic Integration Augmented with Hamiltonian Replica Exchange
ARMY MEDICAL RESEARCH AND MATERIEL COMMAND FORT DETRICK MD
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This paper introduces an efficient single-topology variant of Thermodynamic Integration TI for computing relative transformation free energies in a series of molecules with respect to a single reference state. The presented TI variant that we refer to as Single-Reference TI SR-TI combines well-established molecular simulation methodologies into a practical computational tool. Augmented with Hamiltonian Replica Exchange HREX, the SR-TI variant can deliver enhanced sampling in select degrees of freedom. The utility of the SR-TI variant is demonstrated in calculations of relative solvation free energies for a series of benzene derivatives with increasing complexity. Of note, the SR-TI variant with the HREX option provides converged results in a challenging case of an amide molecule with a high 13-15 kcalmol barrier for internal cistrans interconversion using simulation times of only 1 to 4 ns.
- Medicine and Medical Research
- Physical Chemistry
- Atomic and Molecular Physics and Spectroscopy