Enhanced configurational sampling in binding free-energy calculations

Abstract

The newly developed method of replica-exchange thermodynamic integration (RETI) was tested and compared with finite-difference thermodynamic integration (FDTI) on the calculation of the relative binding free energies of halides to a calix[4]pyrrole derivative. The calculation was challenging, because the dimethylsulfoxide solvent was contaminated by small amounts of water. The lambda-swap move of RETI enabled more-complete sampling of the solvents and produced relative binding free energies that included the effect of the fluoride's higher affinity for water. In addition, the lambda-swap move increased the quality of the configurational sampling of the host, because the system was able to escape from local minima. The results demonstrate that the sampling of RETI is superior to that of FDTI, at no additional computational expense