Combination of alchemical free energy simulation and metadynamics in the simulation package GROMACS
Petr Hošek, Vojtěch Spiwok
Department of Biochemistry and Microbiology, Institute of Chemical Technology, Prague, Technická 3, Prague 6, 166 28, Czech Republic
In recent years, there have been a massive development of various computational method for prediction of binding constants of ligand and proteins, mainly for drug design application. One of these methods is free energy perturbation, method for calculating free energy difference between two chemical distinct systems. Free energies comparable with experimental values can be obtained employing a suitable thermodynamic cycle. The main drawback of free energy perturbation is necessity to know a suitable path connecting both terminal states and select several points on this path for intermediate simulations. This problem do not apply to metadynamics, however classical metadynamic method is not designed to change chemical properties of atoms. The aim of this study is to expand classical metadynamics by adding ability to change one atom into another. Unlike other metadynamics parameters, which can be calculated from coordinates of the studied system, lambda value needs to be handled differently. There are several approaches to handle lambda that ensure driving lambda to potential minima, the first evaluated approach used a simple gradient. Next task was to evaluate and handle associated problems such as the fact that the interval of allowed lambdas is closed or combination of lambda with standard parameters in a multidimensional metadynamics.
The results of this method were compared to experimental values and FEP results of several residue-side-chain solvation energies.