Prediction of CB[8] host–guest binding free energies in SAMPL6 using the double-decoupling method

Han, Kyungreem; Hudson, Phillip S.; Jones, Michael R.; Nishikawa, Naohiro; Tofoleanu, Florentina; Brooks, Bernard R.

doi:10.1007/s10822-018-0144-8

Cited by 14 publications

(28 citation statements)

References 83 publications

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“…A variety of techniques for computing absolute binding free energies have been applied to host-guest systems, and some have shown accuracy as good as ~1 kcal/mol, as highlighted in the recent SAMPL5 and SAMPL6 blind challenges 1,8 . The techniques applied to this problem have included both quantum and classical dynamics, employing a range of energy and solvation models, with some techniques having knowledge-based steps, docking, or clustering [9][10][11][12][13][14][15][16] . The attach-pull-release (APR) method has consistently been ranked among the most reliable techniques for predicting binding thermodynamics of host-guest complexes in blind challenges 8,17 .…”

Section: Introductionmentioning

confidence: 99%

Binding Thermodynamics of Host–Guest Systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

Slochower

Henriksen

Wang

et al. 2019

J. Chem. Theory Comput.

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Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in smallmolecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a drug-like guest molecules have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose systems that avoid ambiguities in protonation states. These features, combined with their ease of experimental characterization, make host-guest systems ideal model systems to test and ultimately optimize force fields in the context of binding thermodynamics calculations.The Open Force Field Initiative aims to create a modern, open software infrastructure for automatically generating and assessing force fields using data sets. The first force field to arise out of this effort, named SMIRNOFF99Frosst, has approximately one tenth the number of parameters, in version 1.0.5, compared to typical general small molecule force fields, such as GAFF. Here, we evaluate the accuracy of this initial force field, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs for which experimental thermodynamic data are available, and compare with matched calculations using two versions of GAFF. For all three force fields, we used TIP3P water and AM1-BCC charges. The calculations are performed using the attach-pull-release (APR) method as implemented in the open source package, pAPRika. For binding free energies, the root mean square error of the SMIRNOFF99Frosst calculations relative to experiment is 0.9 [0.7, 1.1] kcal/mol, while the corresponding results for GAFF 1.7 and GAFF 2.1 are 0.9 [0.7, 1.1] kcal/mol and 1.7 [1.5, 1.9] kcal/mol, respectively, with 95% confidence ranges in brackets. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.

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Section: Introductionmentioning

confidence: 99%

Binding Thermodynamics of Host–Guest Systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

Slochower

Henriksen

Wang

et al. 2019

J. Chem. Theory Comput.

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“…3), for which details can be found in Ref. [41]. Once charge determination was completed, LJ parameters were used directly from CGenFF via the ParamChem server [38, 52].…”

Section: Methodsmentioning

confidence: 99%

“…Once a complete parameter set was obtained for all guest and host of interests, we sought to answer two questions: how well do the parameters perform obtained directly from FM, and does attempting to correct to QM/MM result in an improvement? Free energies computed without applying a correction scheme (i.e., purely classical calculations), were performed using the double decoupling method (DDM) [39, 40], and are detailed in the work published in Ref [41]. However, pursuant to the latter goal of utilizing a correction scheme in the host-guest calculation, the work herein focuses solely on the correction from free energies obtained with a force matched parameter set (i.e., the results of Ref [41]) to QM/MM in a similar manner to Fig 1.…”

Section: Introductionmentioning

confidence: 99%

Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale

Hudson

Han

Woodcock

et al. 2018

J Comput Aided Mol Des

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Use of Quantum Mechanical/Molecular Mechanical (QM/MM) methods in binding free energy calculations, particularly in the SAMPL challenge, often fail to achieve improvement over standard additive (MM) force fields. Frequently, the implementation is through use of reference potentials, or the so-called “indirect approach”, and inherently relies on sufficient overlap existing between MM and QM/MM configurational spaces. This overlap is generally poor, particularly for the use of free energy perturbation to perform the MM to QM/MM free energy correction at the end states of interest (e.g., bound and unbound states). However, by utilizing MM parameters that best reproduce forces obtained at the desired QM level of theory, it is possible to lessen the configurational disparity between MM and QM/MM. To this end, we sought to use force matching to generate MM parameters for the SAMPL6 CB[8] host-guest binding challenge, classically compute binding free energies, and apply energetic end state corrections to obtain QM/MM binding free energy differences. For the standard set of 11 molecules and the bonus set (including 3 additional challenge molecules), error statistics, such as the root mean square deviation (RMSE) were moderately poor (5.5 and 5.4 kcal/mol). Correlation statistics, however, were in the top 2 for both standard and bonus set submissions (R2 of 0.42 and 0.26, τ of 0.64 and 0.47 respectively). High RMSE and moderate correlation strongly indicated the presence of systematic error. Identifiable issues were ameliorated for 2 of the guest molecules, resulting in a reduction of error and pointing to strong prospects for future use of this methodology.

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“…Results from a similar approach applied to the CB8 host can be found in a companion paper by Han et al (receipt ID 3z83m) [25]. By way of outline, our two FES protocols: the US with the weighted histogram analysis method (US-WHAM) and the double decoupling method (DDM) with Hamiltonian replica-exchange method and the Bennett acceptance ratio (HREM-BAR) are presented in “Materials and methods“ section.…”

Section: Introductionmentioning

confidence: 99%

“…In this paper, we will discuss our approaches to calculate the absolute binding free energies of the TEMOA host and the eight guests including our submitted results to the SAMPL6 blind challenge. Results from a similar approach applied to the CB8 host can be found in a companion paper by Han et al (receipt ID 3z83m) [25]. By way of outline, our two FES protocols: the US with the weighted histogram analysis method (US-WHAM) and the double decoupling method (DDM) with Hamiltonian replica-exchange method and the Bennett acceptance ratio (HREM-BAR) are presented in “Materials and methods“ section.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the umbrella sampling and the double decoupling method in binding free energy predictions for SAMPL6 octa-acid host–guest challenges

Nishikawa

Han

et al. 2018

J Comput Aided Mol Des

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We calculate the absolute binding free energies of tetra-methylated octa-acids host-guest systems as a part of the SAMPL6 blind challenge (receipt ID vq30p). We employed two different free energy simulation methods, i.e., the umbrella sampling (US) and double decoupling method (DDM). The US method was used with the weighted histogram analysis method (WHAM) (US-WHAM scheme). In the DDM scheme, Hamiltonian replica-exchange method (HREM) was combined with the Bennett acceptance ratio (BAR) (HREM-BAR scheme). We obtained initial binding poses via molecular docking using GalaxyDock-HG program, which is developed for the SAMPL challenge. The root mean square deviation (RMSD) and the mean absolute deviations (MAD) using US-WHAM scheme were 1.33 and 1.02 kcal/mol, respectively. The MAD was the top among all submissions, however the correlation with respect to experiment was unexceptional. While the RMSD and MAD via HREM-BAR scheme were greater than US-WHAM scheme, (i.e., 2.09 and 1.76 kcal/mol), their correlations were slightly better than US-WHAM. The correlation between the two methods was high. Further discussion on the DDM method can be found in a companion paper by Han et al. (receipt ID 3z83m) in the same issue.

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Prediction of CB[8] host–guest binding free energies in SAMPL6 using the double-decoupling method

Cited by 14 publications

References 83 publications

Binding Thermodynamics of Host–Guest Systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

Binding Thermodynamics of Host–Guest Systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale

Comparison of the umbrella sampling and the double decoupling method in binding free energy predictions for SAMPL6 octa-acid host–guest challenges

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