Method for computing ligand - host binding free energies

摘要

Methods and systems for computing the binding free energy of a ligand to a host are disclosed. The method entails selecting random poses of a ligand, including translation, rotation, and conformation, and computing the ligand-host interaction energy. The poses are accepted or rejected based on the Metropolis criteria. The entropies of interaction are estimated from the log of the ratio of accepted poses to attempted poses. The free energy of the entire sampling region, and of sub-regions of the binding region, can be accumulated by storing the energies and acceptance ratios for both the entire region and the sub regions. In order to better shape the protein to the ligand, energy minimization of the host atoms in the region of the ligand is carried out in the presence of the lowest free-energy pose of the ligand, optionally preceded by random perturbation of the Cartesian coordinates of the host atoms in the vicinity of the ligand.