Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host–Guest Binding: III. Force-Field Comparison, Three-Trajectory Realization and Further Dielectric Augmentation

Abstract

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.

Screening Power of End-Point Free-Energy Calculations in Cucurbituril Host–Guest Systems

“…Compared with pillararene host–guest complexes investigated in our previous works, ,, the ranking powers of end-point methods are generally much better in the current cucurbituril data set. This noticeable difference could be possibly related to the successes of error cancellation in specific systems (e.g., force-field applicability, polarization, and approximations introduced in the end-point procedure).…”

“…It impacts the end-point calculation in both the single-and threetrajectory protocols. While the former single-trajectory variable dielectric model is rather common in end-point applications, 65−68 the latter three-trajectory dielectric-constant-varia-ble treatment as a newly introduced regime in our recent work 53 is still not well understood. The current large-scale benchmark on cucurbituril host−guest complexes thus provides a valuable evaluation of this advanced end-point protocol.…”

“…The sampling lengths in host-only, guest-only, and host−guest complex systems are set to 500 ns, 100, and 100 ns according to our recent observation of the complex host dynamics for cucurbiturils 21,30 complexes. 53 The sampling interval of the snapshots is set to 10 ps. The accumulated snapshots are then fed to the end-point free-energy estimation protocol, including MM/PBSA and MM/GBSA with the GB OBC model.…”

“…Therefore, we construct three simulation boxes for each host–guest pair. For the unbound state, the solute (either host or guest) is solvated in the SPC/E water, as the selection of water model does not incur significant differences in the performance of end-point calculations. ,, Neutralization is performed by adding spherical monovalent counterions of Na + or Cl – to the system. As for the host–guest bound state, the initial guess of the bound conformation is obtained via molecular docking with Autodock Vina.…”

“…Each system experiences energy minimization, 300 ps heating, and 1 ns NPT equilibration, after which the NPT production run begins. The sampling lengths in host-only, guest-only, and host–guest complex systems are set to 500 ns, 100, and 100 ns according to our recent observation of the complex host dynamics for cucurbiturils , and higher difficulties of sampling the host-only system in end-point calculations of pillararene host–guest complexes . The sampling interval of the snapshots is set to 10 ps.…”