Understanding the physical forces underlying receptor-ligand binding requires robust methods for analyzing the binding thermodynamics. In end-point methods the binding free energy is naturally decomposable into physically intuitive contributions such as the solvation free energy and configurational entropy that can provide insights. Here we present a new end-point method called EE-BQH (Effective Energy-Boltzmann-Quasiharmonic) which combines the Boltzmann-Quasiharmonic model for configurational entropy with different solvation free energy methods such as the continuum solvent PBSA model and the integral equation-based 3D-RISM to estimate the absolute binding free energy (<i>Phys. Chem. Chem. Phys</i>., 2022, 24, 6037-6052). We compare EE-BQH with other treatments of configurational entropy such as Quasiharmonic models in internal coordinates (QHIC) and in cartesian coordinates (QHCC), and Normal Mode analysis (NMA), by testing them on the octa acids host-guest complexes from the SAMPL8 blind challenge. The accuracies in the calculated absolute binding free energies strongly depend on the configurational entropy and solvation free energy methods used. QHIC and BQH yield the best agreements with the established potential of mean force (PMF) estimates, with R<sup>2</sup> of ~ 0.7 and mean unsigned error of ~ 1.7 kcal/mol. These results from the end-point calculations are also in similar agreement with experiments. While the binding is accompanied by a large reduction in the ligand translational/rotational entropy, the change in the torsional entropy in these host-guest systems is slightly positive. Compared with BQH, QHIC underestimates the reduction of configurational entropy because of the non-Gaussian probability distributions in the ligand rotation and torsional degrees of freedom. The study highlights the crucial role of configurational entropy in determining binding and demonstrates the potential of using the new end-point method to provide insights in more complex protein-ligand systems.

Developing end-point methods for absolute binding free energy and entropy using the Boltzmann-Quasiharmonic model

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