Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: II. regression and dielectric constant

Abstract

End-point free energy calculations as a powerful tool have been widely applied in protein-ligand and protein-protein interactions. It is often recognized that these end-point techniques serve as an option of intermediate accuracy and computational cost compared with more rigorous statistical mechanic models (e.g., alchemical transformation) and coarser molecular docking. However, it is observed that this intermediate level of accuracy does not hold in relatively simple and prototypical host-guest systems. Specifically, in our previous work investigating a set of carboxylated-pillar[6]arene host-guest complexes, end-point methods provide free energy estimates deviating significantly from the experimental reference, and the rank of binding affinities is also incorrectly computed. These observations suggest the unsuitability and inapplicability of standard end-point free energy techniques in host-guest systems, and alteration and 2 / 41 development are required to make them practically usable. In this work, we consider two ways to improve the performance of end-point techniques. The first one is the PBSA_E regression that varies the weights of different free energy terms in the end-point calculation procedure, while the second one is considering the interior dielectric constant as an additional variable in the end-point equation. By detailed investigation of the calculation procedure and the simulation outcome, we prove that these two treatments (i.e., regression and dielectric constant) are manipulating the end-point equation in a somehow similar way, i.e., weakening the electrostatic contribution and strengthening the non-polar terms, although there are still many detailed differences between these two methods. With the trained end-point scheme, the RMSE of the computed affinities is improved from the standard ~12 kcal/mol to ~2.4 kcal/mol, which is comparable to another altered end-point method (ELIE) trained with system-specific data. This phenomenon along with the extremely efficient optimized-structure computation procedure suggests the regression (i.e., PBSA_E as well as its GBSA_E extension) as a practically applicable solution that brings end-point methods back into the library of usable tools for host-guest binding. However, the dielectric-constant-variable scheme cannot effectively minimize the experiment-calculation discrepancy for absolute binding affinities, but is able to improve the calculation of affinity ranks. This phenomenon is somehow different from the protein-ligand case and suggests the difference between host-guest and biomacromolecular (protein-ligand and proteinprotein) cases. Therefore, the spectrum of tools usable in protein-ligand cases could be unsuitable for hostguest binding, and numerical validations are necessary to screen out really workable solutions in these 'prototypical' situations.

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

“…1 are obtained from the GitHub site of the SAMPL9 challenge. 20 Due to the observed similar prediction qualities of commonly employed charge schemes in this dataset, 13,14 we generate atomic charges with the restrained electrostatic potential (RESP) 21 scheme with ESP data scanned at the traditional HF [22][23][24] /6-31G* level (i.e., RESP-1 charge set in our previous works and our GitHub repository for atomic charges https://github.com/proszxppp/WP6-host-guest-binding). As for the other parameters (e.g., bonded terms), following our previous works, 13,14 we take the transferable GAFF2 parameter set 19 and a recent publication extending the GAFF2 parametrization to Si-involved species, 25 forming a GAFF2-host GAFF2-guest modelling protocol.…”

“…The model construction follows our WP6 end-point series works. 13,14 The 3D chemical structures of host and guest molecules shown in Fig. 1 are obtained from the GitHub site of the SAMPL9 challenge.…”

“…As a testing bed of common interest, the carboxylated-pillar [6]arene (WP6) host-guest dataset in the recent SAMPL9 challenge has been employed to benchmark the performance of various end-point procedures in our recent works, where extensive numerical data suggest the unsuitability of standard end-point calculation for host-guest binding. 13,14 To provide really meaningful predictions, alterations seem necessary. In the context of protein-ligand binding, there are a spectrum of modifications of the end-point procedure in order to achieve higher accuracy.…”

“…One altered regime that achieves pronounced improvements for both absolute and relative values is regression, and the dielectric-constant-variable regime that is widely employed in endpoint free energy calculations performs rather poorly and marginally betters the ranking calculation. 13 The underperformance of the dielectric-constant regime is to some extent conflicting with protein-ligand situations, which again hints at the different behaviors of host-guest and biomacromolecular systems.…”

“…Differences between GAFF and GAFF2 for the macrocyclic host are identified in many aspects, which could have significant impacts on the end-point estimates of binding affinities. As we only focus on the charge scheme, water model and docking procedure in model construction and overlook this critical GAFF-version comparison in our previous works, 13,14 we add a benchmark on the popular GAFF versions in single-trajectory end-point calculations, as a crucial addition to the influencing factors in standard end-point calculations. Then, the three-trajectory realization of end-point free energy calculations under transferable GAFF derivatives is conducted and a detailed investigation of energetic behaviors is presented.…”