Title: 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.