Combining Alchemical Transformation with Physical Pathway to Accurately Compute Absolute Binding Free Energy

Abstract

We present a new method that combines alchemical transformation with physical pathway to accurately and efficiently compute the absolute binding free energy of receptor-ligand complex. Currently, the double decoupling method (DDM) and the potential of mean force approach (PMF) methods are widely used to compute the absolute binding free energy of biomolecules. The DDM relies on alchemically decoupling the ligand from its environments, which can be computationally challenging for large ligands and charged ligands because of the large magnitude of the decoupling free energies involved. On the other hand, the PMF approach uses physical pathway to extract the ligand out of the binding site, thus avoids the alchemical decoupling of the ligand. However, the PMF method has its own drawback because of the reliance on a ligand binding/unbinding pathway free of steric obstruction from the receptor atoms. Therefore, in the presence of deeply buried ligand functional groups the convergence of the PMF calculation can be very slow leading to large errors in the computed binding free energy. Here we develop a new method called AlchemPMF by combining alchemical transformation with physical pathway to overcome the major drawback in the PMF method. We have tested the new approach on the binding of a charged ligand to an allosteric site on HIV-1 Integrase. After 20 ns of simulation per umbrella sampling window, the new method yields absolute binding free energies within ~1 kcal/mol from the experimental result, whereas the standard PMF approach and the DDM calculations result in errors of ~5 kcal/mol and > 2 kcal/mol, respectively. Furthermore, the binding free energy computed using the new method is associated with smaller statistical error compared with those obtained from the existing methods.