Extending the scope of alchemical perturbation methods for ligand binding free energy calculations

Abstract: Previously, a method for computing binding free energies between different poses of a ligand bound to a protein using alchemical perturbation was developed. The methodology is to perturb the ligand into a smaller version, common to both poses, from which the difference in free energy between poses can be computed. Here, the method is further improved by finding low-error setups for the method, by investigating different kinds of restraints put on the system during simulation and different kinds of parameters for the soft-core potential. The best low-error setup found was using a 1-1-48 soft-core potential with a water barrier and positional restraints for all the non-hydrogen atoms in the system. Instability was detected for one of the poses, this was investigated. The key to having a stable pose seems to be to understand the effect on stability of changing the Ryckaert-Bellemans parameters for a single rotatable bond.