Testing and Comparing approaches for conformational sampling in Alchemical Binding Free Energy calculations

Post date: Jun 22, 2020 6:03:45 PM by Sheenam

Finding the true binding free energy of a protein-ligand complex remains a crucial challenge in the field of computer-aided drug design. This is the case even for simple systems. One of the key factors to obtaining reliable binding free energy estimates is an adequate sampling of the protein side chains, which if not accounted for, can give an error in binding free energy values by several kcal/mol. To address this problem, here we test a heating & cooling conformational sampling strategy where we heat the system to enable side chains motions and then cool it before production at room temperature. We incorporate this conformational sampling strategy in our alchemical binding free energy estimation protocol and we apply it to a well-known benchmark system: the complex of the L99A mutant of T4 lysozyme with small organic molecules which display varying configurations of protein side chains. We show that unlike the standard calculations at a single temperature, the heating & cooling methodology explores multiple conformations and returns converged binding free energy estimates independent of the starting conformation.

Fig. 3: Orientation of p-xylene with Val111 sidechain in the modeled structure of  T4L99A observed at two main conformations A. trans B. gauche.