<scp>NE‐RDFE</scp>: A protocol and toolkit for computing relative dissociation free energies with <scp>GROMACS</scp> between dissimilar molecules using bidirectional nonequilibrium dual topology schemes

Macchiagodena, Marina; Pagliai, Marco; Procacci, Piero

doi:10.1002/jcc.27077

Cited by 3 publications

(2 citation statements)

References 49 publications

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“…The end-point estimators are often fed with coarser docking or machine-learning outcomes, rerank the candidates, and then distill a smaller set of potentially promising compounds. While the screening power and applicability of end-point protocols have been validated in biomacromolecular assemblies, − the practical performance of end-point methods in host–guest complexes is generally not well understood. Although many end-point results have been reported in scientific publications, obvious system- and protocol-dependent behaviors of the end-point accuracy could be observed.…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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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“…Water-soluble pillar[n]arenes have grown to be a crucial macrocycle family with wide applications in drug delivery and material research [26][27][28][29]. The host-guest dataset involving the 6-unit carboxylated pillararene (WP6) from the SAMPL9 challenge, as a good testing bed for free energy techniques, has been extensively investigated in our end-point series [30][31][32], as well as many others [33,34]. Standard end-point applications seem useless in predictions of both absolute affinities and their relative ranks and are even worse than docking scores [31], while modified regimes, especially the three-trajectory realization, perform quite well in rank predictions [30,32].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-Guest Binding: IV. The QM Treatment, GB Models and the Multi-Trajectory Extension

Wang,

Sun

2023

Liquids

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Due to the similarity of host–guest complexes and protein–ligand and protein–protein assemblies, computational tools for protein–drug complexes are commonly applied in host–guest binding. One of the methods with the highest popularity is the end-point free energy technique, which estimates the binding affinity with gas-phase and solvation contributions extracted from simplified end-point sampling. Our series papers on a set of carboxylated-pillararene host–guest complexes have proven with solid numerical evidence that standard end-point techniques are practically useless in host–guest binding, but alterations, such as slightly increasing interior dielectric constant in post-processing calculation and shifting to the multi-trajectory realization in conformational sampling, could better the situation and pull the end-point method back to the pool of usable tools. Also, the force-field selection plays a critical role, as it determines the sampled region in the conformational space. In the current work, we continue the efforts to explore potentially promising end-point modifications in host–guest binding and further extend the sampling time to an unprecedent length. Specifically, we comprehensively benchmarked the shift from the original MM description to QM Hamiltonians in post-processing the popular single-trajectory sampling. Two critical settings in the multi-scale QM/GBSA regime are the selections of the QM Hamiltonian and the implicit-solvent model, and a scan of combinations of popular semi-empirical QM Hamiltonians and GB models is performed. The multi-scale QM/GBSA treatment is further combined with the three-trajectory sampling protocol, introducing a further advanced modification. The sampling lengths in the host–guest complex, solvated guest and solvated host ensembles are extended to 500 ns, 500 ns and 12,000 ns. As a result, the sampling quality in end-point calculations is unprecedently high, enabling us to draw conclusive pictures of investigated forms of modified end-point free energy methods. Numerical results suggest that the shift to the QM Hamiltonian does not better the situation in the popular single-trajectory regime, but noticeable improvements are observed in the three-trajectory sampling regime, especially for the DFTB/GBSA parameter combination (either DFTB2 or its third-order extension), the quality metrics of which reach an unprecedently high level and surpass existing predictions (including costly alchemical transformations) on this dataset, hinting on the applicability of the advanced three-trajectory QM/GBSA end-point modification for host–guest complexes.

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Multi-temperature charge scaling of ionic solvents: Disparate responses of thermodynamic properties

Wang,

Liu,

et al. 2024

Journal of Molecular Liquids

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NE‐RDFE: A protocol and toolkit for computing relative dissociation free energies with GROMACS between dissimilar molecules using bidirectional nonequilibrium dual topology schemes

Cited by 3 publications

References 49 publications

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

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

Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-Guest Binding: IV. The QM Treatment, GB Models and the Multi-Trajectory Extension

Multi-temperature charge scaling of ionic solvents: Disparate responses of thermodynamic properties

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