Molecular dynamics based free energy calculations allow the determination of a variety of thermodynamic quantities from computer simulations of small molecules. Thermodynamic integration (TI) calculations can suffer from instabilities during the creation or annihilation of particles. This ‘singularity’ problem can be addressed with soft-core potential functions which keep pairwise interaction energies finite for all configurations and provide smooth free energy curves. “One-step” transformations, in which electrostatic and van der Waals forces are simultaneously modified, can be simpler and less expensive than “two-step” transformations in which these properties are changed in separate calculations. Here we study solvation free energies for molecules of different hydrophobicity using both models. We provide recommended values for the two parameters αLJ and βC controlling the behaviour of the soft-core Lennard-Jones and Coulomb potentials and compare one-step and two-step transformations with regard to their suitability for numerical integration. For many types of transformations, the one-step procedure offers a convenient and accurate approach to free energy estimates.
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