Free energy perturbation calculations involving potential function changes

Abstract

AbstractThe solvation free energies of thymine and adenine were calculated using free energy methods to examine the effect of applying Lennard–Jones 6‐12 and 10‐12 perturbations to the hydrogen‐bonding groups. The calculations were performed using a new free energy algorithm developed for the AMBER 4.0 program package that allows an interaction described by a Lennard–Jones 6‐12 potential to be changed into one described by a hydrogen bond 10‐12 potential. The algorithm applied allows this change to occur smoothly without the generation of more extrema on the potential surface. Results using this algorithm have been compared with those determined using the standard AMBER 3.0 Revision A program package, which provides for 6‐12 to 6‐12 parameter perturbations only. We have also developed a procedure to perform pyrimidine to purine nucleoside mutations to calculate the relative free energies of solvation directly. The theoretical results are compared to experimental energies derived from solvation and vaporization data taken from the literature. The free energies calculated using the new algorithm show good agreement with the derived experimental values. This is also true for the calculations that employ the 6‐12 function only, but with 6‐12 parameters modified to reflect the correct hydrogen‐bonding interactions. However, perturbation of the “standard” 6‐12 parameters without changing the functional form proves to be less effective in determining solvation free energies correctly, and demonstrates the importance of accurate hydrogen bond descriptions in free energy simulations.