SITE-SPECIFIC FRAGMENT IDENTIFICATION GUIDED BY SINGLE-STEP FREE ENERGY PERTURBATION CALCULATIONS

摘要

A method and system is disclosed for estimating the difference between binding free energies of molecules.

主权项

1. A method for estimating the difference between binding free energies of molecules, said method carried out on a computer and comprising:
carrying out a molecular dynamics simulation or a Monte Carlo simulation on a large molecule and at least one small molecule, wherein the small molecule is not an unphysical reference state, to obtain multiple conformations of said large and small molecules in a binding environment of the large molecule; determining an energy of the small molecule in said binding environment for said conformations; replacing one or more atoms of said small molecule with one or more different atoms for each of said conformations, to obtain a modified small molecule in said binding environment; determining an energy of the modified small molecule in said binding environment for said conformations, wherein a molecular dynamics simulation or Monte Carlo simulation is not carried out on said modified small molecule; and carrying out a single step perturbation calculation using said energies of the small and modified small molecules, to obtain the estimated difference between the binding free energies of said small and modified small molecules to said large molecule.