No abstract

Despite the massive application of end-point free energy methods in protein-ligand and protein-protein interactions, computational understandings about their performance in relatively simple and prototypical host-guest systems are limited. In this work, we present a comprehensive benchmark calculation with standard end-point free energy techniques in a recent host-guest dataset containing 13 host-guest pairs involving the carboxylated-pillar[6]arene host. We first assess the charge schemes for solutes by comparing the charge-produced electrostatics with many ab initio references, in order to obtain a preliminary albeit detailed view of the charge quality. Then, we focus on four modelling details of end-point free energy calculations, including the docking procedure for the generation of initial condition, the charge scheme for host and guest molecules, the water model used in explicit-solvent sampling, and the end-point methods for free energy estimation. The binding thermodynamics obtained with different modelling schemes are compared with experimental references, and some practical guidelines on maximizing the performance of end-point methods in practical host-guest systems are summarized. Finally, we compare our simulation outcome with predictions in the grand challenge and discuss further developments to improve the prediction quality of end-point free energy methods.

Host–guest binding, despite the relatively simple structural and chemical features of individual components, still poses a challenge in computational modelling. The extreme underperformance of standard end-point methods in host–guest binding makes them practically useless. In the current work, we explore a potentially promising modification of the three-trajectory realization. The alteration couples the binding-induced structural reorganization into free energy estimation and suffers from dramatic fluctuations in internal energies in protein–ligand situations. Fortunately, the relatively small size of host–guest systems minimizes the magnitude of internal fluctuations and makes the three-trajectory realization practically suitable. Due to the incorporation of intra-molecular interactions in free energy estimation, a strong dependence on the force field parameters could be incurred. Thus, a term-specific investigation of transferable GAFF derivatives is presented, and noticeable differences in many aspects are identified between commonly applied GAFF and GAFF2. These force-field differences lead to different dynamic behaviors of the macrocyclic host, which ultimately would influence the end-point sampling and binding thermodynamics. Therefore, the three-trajectory end-point free energy calculations are performed with both GAFF versions. Additionally, due to the noticeable differences between host dynamics under GAFF and GAFF2, we add additional benchmarks of the single-trajectory end-point calculations. When only the ranks of binding affinities are pursued, the three-trajectory realization performs very well, comparable to and even better than the regressed PBSA_E scoring function and the dielectric constant-variable regime. With the GAFF parameter set, the TIP3P water in explicit solvent sampling and either PB or GB implicit solvent model in free energy estimation, the predictive power of the three-trajectory realization in ranking calculations surpasses all existing end-point methods on this dataset. We further combine the three-trajectory realization with another promising modified end-point regime of varying the interior dielectric constant. The combined regime does not incur sizable improvements for ranks and deviations from experiment exhibit non-monotonic variations.

Host-guest binding, despite the relatively simple structural and chemical features of individual components, still poses a challenge in computational modelling. The problems lie in both the accuracy of the employed Hamiltonian (often fixed-charge force fields) and the exhaustiveness of conformational sampling. End-point free energy calculations as fast alternatives to rigorous but costly methods are widely applied in virtual screening in protein-ligand and host-guest systems. However, the extreme underperformance of standard end-point methods makes them practically useless. Modifications of the end-point procedure could bring these methods back to the pool of usable tools, e.g., regression considered in our previous work. In the current work, we explore a potentially promising modification, the three-trajectory realization of the end-point simulation protocol. The alteration couples the binding-induced structural reorganization into free energy estimation and suffers from dramatic fluctuations of internal energies in protein-ligand situations. Fortunately, the relatively small size of host-guest systems minimizes the magnitude of internal fluctuations and makes the three-trajectory realization practically suitable. Due to the incorporation of intra-molecular interactions in free energy estimation, a strong dependence on the force field parameters could be incurred. Thus, a term-specific investigation of transferable GAFF derivatives is presented, and noticeable differences in many aspects are identified between commonly applied GAFF and GAFF2. These force-field differences lead to different dynamic behaviors of the macrocyclic host, which ultimately would influence the end-point sampling and binding thermodynamics. Therefore, the three-trajectory end-point free energy calculations are performed with both GAFF versions to investigate the force-field dependent behavior of computed binding affinities. Also, due to the noticeable differences between host dynamics under GAFF and GAFF2, we add additional benchmarks of the single-trajectory end-point calculations. Numerical results suggest that the single-trajectory realization, regardless of the GAFF version, is still not useful in host-guest binding, although the prediction quality of the GAFF2 parameter set is slightly better than GAFF. As for the three-trajectory realization, the absolute values of computed binding thermodynamics exhibit pronounced force-field-dependent behaviors, which are less significant for ranking information. When only the ranks of binding affinities are pursued, the three-trajectory realization performs very well, comparable to and even better than the regressed PBSA_E scoring function and the dielectric-constant-variable regime. With the GAFF parameter set, the TIP3P water in explicit-solvent sampling and either PB or GB implicit-solvent model in free energy estimation, the predictive power of the three-trajectory realization in ranking calculations surpasses all existing end-point methods on this dataset. We further combine the three-trajectory realization with another promising modified end-point regime of varying the interior dielectric constant. The predicted binding affinities exhibit monotonic responses to the variation of the internal dielectric constant, but the deviations from experiment exhibit non-monotonic variations, which are related to the systematic overestimation of the binding strength under the original three-trajectory realization. By contrast, the combined regime does not incur sizable improvements for ranks, although for most systems the dielectric constant 2 seems to be the best option.