Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: I. Standard procedure

Liu, Xiao; Zheng, Lei; Qin, Chu; Zhang, John Z. H.; Sun, Zhaoxi

doi:10.1007/s10822-022-00475-0

Cited by 9 publications

(44 citation statements)

References 132 publications

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“…The system construction follows exactly the same protocol used in our previous work. 53 Briefly, the 3D chemical structures of all molecules shown in Fig. 1 are grabbed from the GitHub site of the SAMPL9 challenge.…”

Section: Model Constructionmentioning

confidence: 99%

“…Two RESP charge sets are generated due to their noticeable difference in the electrostatic potential (ESP) around each molecule observed in our previous work. 53 The fitting target of the RESP-1 charge set is the molecular ESP scanned at the traditional HF [61][62][63] /6-31G*, while the target level of the second RESP charge set (RESP-2) is B3LYP [64][65][66] /def2-TZVPP with the IEFPCM implicit solvent. All the other missing force-field parameters are obtained from the second generation of the general AMBER force field (GAFF2) 67 and a recent publication adding the parameters for Si-related species.…”

Section: Model Constructionmentioning

confidence: 99%

“…The bound structure of each host-guest complex remains unknown, which is often solved via molecular docking. Following our previous work, 53 we use the Autodock Vina 72 program to generate the initial guess, i.e., picking the top-1 (the most stable) structure provided by docking. As the starting configuration could have a significant impact on the simulation outcome, especially when the simulation is performed in an unbiased way.…”

Section: Model Constructionmentioning

confidence: 99%

“…Possible reasons causing the underperformance of end-point calculations in host-guest complex along with further directions for developments have been discussed extensively in our previous work. 53 In the current work, building on previous observations of the standard end-point procedure, we expect to extend the evaluation by considering two altered regimes that could lead to improved performance. Specifically, we consider the regression and dielectric-constant-variable alterations that change the weights of free energy terms in the end-point calculation.…”

mentioning

confidence: 99%

“…In a recent work, we report a thorough evaluation of end-point methods with the standard (popular) procedure in a set of WP6 host-guest systems. 53 Specifically, we consider four modelling details including the scoring function used in docking (two scoring functions), the charge scheme for solutes (three charge sets), the water model for solvation (two water models), and the end-point method used in free energy estimation (two endpoint schemes). The resulting calculation regimes include 24 combinations, covering almost all popular selections in modern researches.…”

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confidence: 99%

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Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-guest Binding: II. Regression and Dielectric Constant

Liu

Zheng

Cong

et al. 2022

Preprint

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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 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 protein-protein) cases. Therefore, the spectrum of tools usable in protein-ligand cases could be unsuitable for host-guest binding, and numerical validations are necessary to screen out really workable solutions in these ‘prototypical’ situations.

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Section: Model Constructionmentioning

confidence: 99%

Section: Model Constructionmentioning

confidence: 99%

Section: Model Constructionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-guest Binding: II. Regression and Dielectric Constant

Liu

Zheng

Cong

et al. 2022

Preprint

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Exploring the role of microbial proteins in controlling environmental pollutants based on molecular simulation

Wu,

Lv,

Zhao

et al. 2023

Science of The Total Environment

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

Liu,

Zheng,

Qin

et al. 2023

J. Chem. Inf. Model.

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End-point free-energy methods as an indispensable component in virtual screening are commonly recognized as a tool with a certain level of screening power in pharmaceutical research. While a huge number of records could be found for end-point applications in protein–ligand, protein–protein, and protein–DNA complexes from academic and industrial reports, up to now, there is no large-scale benchmark in host–guest complexes supporting the screening power of end-point free-energy techniques. A good benchmark requires a data set of sufficient coverage of pharmaceutically relevant chemical space, a long-time sampling length supporting the trajectory approximation of the ensemble average, and a sufficient sample size of receptor–acceptor pairs to stabilize the performance statistics. In this work, selecting a popular family of macrocyclic hosts named cucurbiturils, we construct a large data set containing 154 host–guest pairs, perform extensive end-point sampling of several hundred nanosecond lengths for each system, and extract the free-energy estimates with a variety of end-point free-energy techniques, including the advanced three-trajectory dielectric-constant-variable regime proposed in our recent work. The best-performing end-point protocol employs GAFF2 for solute descriptions, the three-trajectory end-point sampling regime, and the MM/GBSA Hamiltonian in free-energy extraction, achieving a high ranking metrics of Kendall τ > 0.6, a Pearlman predictive index of ∼0.8, and a high scoring power of Pearson r > 0.8. The current project as the first large-scale systematic benchmark of end-point methods in host–guest complexes in academic publications provides solid evidence of the applicability of end-point techniques and direct guidance of computational setups in practical host–guest systems.

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Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: I. Standard procedure

Cited by 9 publications

References 132 publications

Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-guest Binding: II. Regression and Dielectric Constant

Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-guest Binding: II. Regression and Dielectric Constant

Exploring the role of microbial proteins in controlling environmental pollutants based on molecular simulation

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

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