Validation and Comparison of Force Fields for Native Cyclodextrins in Aqueous Solution

Gebhardt, Julia; Kleist, Catharina; Jakobtorweihen, Sven; Hansen, Niels

doi:10.1021/acs.jpcb.7b11808

Cited by 50 publications

(60 citation statements)

References 184 publications

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“…The combination of X-ray and NMR data suggest that the specialized q4md-CD 51 force field, and the rigid GAFF v2.1 33 force field, better model the flexibility of the CD cavity. The CHARMM36 force field displays similar structural dynamics to q4md-CD, with certain GROMOS force fields even more rigid than those 53 . The present results suggest that, as SMIRNOFF99Frosst is further developed, it will be important to include sugars and other carbohydrates in the training sets used to develop parameters.…”

Section: Discussionmentioning

confidence: 91%

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: Discussionmentioning

confidence: 91%

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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“…[53] This is apparent from the tumbling of glucoside units,w hich bend outwards and distortt he conical shape and the hydrogen-bondingn etwork. [49] Indeed, our analysisr eveals thats pecifically the fucosylated glucoside units show enhancedr otation andi ncreased chair flexibility.T hese tilted states are not frequent, but are stable over several nanoseconds ( Figure S4). The tilting of the cyclodextrin ring sugars is more pronounced upon fucosylation (Figure 4), which can be seen from the enhanced probability of finding the dihedrala ngles connecting Glc units G-A (blue dashed line) and C-D (orange dashed line) at values of 60-90 degrees away from the main peak.…”

Section: Resultsmentioning

confidence: 73%

Direct and Regioselective Di‐α‐fucosylation on the Secondary Rim of β‐Cyclodextrin

Verkhnyatskaya

Vries

et al. 2019

Chemistry A European J

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A straightforward glycosylation method is described to regio‐ and stereoselectively introduce two α‐ l ‐fucose moieties directly to the secondary rim of β‐cyclodextrin. Using NMR and MS fragmentation studies, the nonasaccharide structure was determined, which was also visualized using molecular dynamics simulations. The reported glycosylation method proved to be robust on gram‐scale, and may be generally applied to directly glycosylate β‐cyclodextrins to make well‐defined multivalent glycoclusters.

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“…Previous work has also noted the existence of these two conformations in explicit solvent with different force fields and water models. 37,45,67 The displacement of water from the interior of the cavity plays a critical role in the reorganization mechanism of β-CD from open to closed conformations. Water molecules enclosed in the host cavity experience unfavorable free energies relative to bulk water.…”

Section: Discussionmentioning

confidence: 99%

The Role of Displacing Confined Solvent in the Conformational Equilibrium of β-Cyclodextrin

He¹,

Sarkar²,

Gallicchio³

et al. 2019

Preprint

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This study investigates the role of hydration and its relationship to the conformational equilibrium of the host molecule β-cyclodextrin. Molecular dynamics simulations indicate that the unbound βcyclodextrin exhibits two state behavior in explicit solvent due to the opening and closing of its cavity. In implicit solvent, these transitions are not observed and there is one dominant conformation of β-cyclodextrin with an open cavity. Based on these observations, we investigate the hypothesis that the expulsion of thermodynamically unfavorable water molecules into the bulk plays an important role in controlling the accessibility of the closed macrostate at room temperature. We compare the results of the molecular mechanics analytical generalized Born plus non-polar solvation approach to those obtained through Grid Inhomogeneous Solvation Theory analysis with explicit solvation to elucidate the thermodynamic forces at play. The calculations help to illustrate the deficiencies of continuum solvent models and demonstrate the key role of the thermodynamics of enclosed hydration in driving the conformational equilibrium of molecules in solution.

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Validation and Comparison of Force Fields for Native Cyclodextrins in Aqueous Solution

Cited by 50 publications

References 184 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

Direct and Regioselective Di‐α‐fucosylation on the Secondary Rim of β‐Cyclodextrin

The Role of Displacing Confined Solvent in the Conformational Equilibrium of β-Cyclodextrin

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