Toward Expanded Diversity of Host-Guest Interactions via Synthesis and Characterization of Cyclodextrin Derivatives

Kellett, Kathryn; Kantonen, Samuel A.; Duggan, Brendan M.; Gilson, Michael K.

doi:10.26434/chemrxiv.5782224

Cited by 6 publications

(10 citation statements)

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“…It should be straightforward to expand this approach by using additional data from the experimental literature. In addition, we have embarked on a project to generate new experimental host-guest data specifically designed to generate a diverse collection of chemical interactions that will be useful to test and improve force fields 70 .…”

Section: Discussionmentioning

confidence: 99%

“…However, we anticipate that substantial reductions in scatter will require coordinated, consistent adjustments of both water and solute parameters. Using binding data to adjust solute force field parameters will require a larger dataset of binding thermodynamics, so, as noted above, our group is working to systematically expand the dataset by developing facile syntheses of cyclodextrin derivatives designed to probe diverse nonbonded interactions 70 . We anticipate that force fields adjusted based on the resulting data will improve the accuracy of computed free energies not only for host-guest systems, but also for protein-ligand interactions important in drug design and discovery.…”

Section: Discussionmentioning

confidence: 99%

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Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

Yin

Henriksen

Muddana

et al. 2018

J. Chem. Theory Comput.

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We report a water model, Bind3P (Version 0.1), which was obtained by using sensitivity analysis to readjust the Lennard-Jones parameters of the TIP3P model against experimental binding free energies for six host-guest systems, along with pure liquid properties. Tests of Bind3P against >100 experimental binding free energies and enthalpies for host-guest systems distinct from the training set show a consistent drop in the mean signed error, relative to matched calculations with TIP3P. Importantly, Bind3P also yields some improvement in the hydration free energies of small organic molecules and preserves the accuracy of bulk water properties, such as density and the heat of vaporization. The same approach can be applied to more sophisticated water models that can better represent pure water properties. These results lend further support to the concept of integrating host-guest binding data into force field parametrization.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

Yin

Henriksen

Muddana

et al. 2018

J. Chem. Theory Comput.

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“…In the simulations we probed two guest orientations: primary orientation (hydroxy group of g1 and amine of g2 oriented towards the primary face) and secondary orientation (hydroxy group of g1 and amine of g2 oriented towards the secondary face) (b) latest version of the SAMPL7 challenge's GitHub repository were used. Initial structures were generated by positioning the guest so its center of geometry equals to that of the host while the amine (for R-rimantadine) and hydroxyl (for trans-4-methylcyclohexanol) were pointing to the primary or secondary cyclodextrin face [22]. In the calculation we explicitly probed two orientations, corresponding to two possible binding poses, for each host-guest system (Fig.…”

Section: Initial Simulationsmentioning

confidence: 99%

Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software

Khalak

Tresadern

Groot

et al. 2020

J Comput Aided Mol Des

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In the current work we report on our participation in the SAMPL7 challenge calculating absolute free energies of the host–guest systems, where 2 guest molecules were probed against 9 hosts-cyclodextrin and its derivatives. Our submission was based on the non-equilibrium free energy calculation protocol utilizing an averaged consensus result from two force fields (GAFF and CGenFF). The submitted prediction achieved accuracy of $${1.38}\,\hbox {kcal}/\hbox {mol}$$ 1.38 kcal / mol in terms of the unsigned error averaged over the whole dataset. Subsequently, we further report on the underlying reasons for discrepancies between our calculations and another submission to the SAMPL7 challenge which employed a similar methodology, but disparate ligand and water force fields. As a result we have uncovered a number of issues in the dihedral parameter definition of the GAFF 2 force field. In addition, we identified particular cases in the molecular topologies where different software packages had a different interpretation of the same force field. This latter observation might be of particular relevance for systematic comparisons of molecular simulation software packages. The aforementioned factors have an influence on the final free energy estimates and need to be considered when performing alchemical calculations.

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Section: Discussionmentioning

confidence: 99%

Bind3P: Optimization of a Water Model with Host-Guest Binding Data

Yin

Nm²,

Hs³

et al. 2018

Preprint

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We report a water model, Bind3P (Version 0.1), which was obtained by using sensitivity analysis to readjust the Lennard-Jones parameters of the TIP3P model against experimental binding free energies for six host-guest systems, along with pure liquid properties. Tests of Bind3P against >100 experimental binding free energies and enthalpies for host-guest systems distinct from the training set show a consistent drop in the mean signed error, relative to matched calculations with TIP3P. Importantly, Bind3P also yields some improvement in the hydration free energies of small organic molecules, and preserves the accuracy of bulk water properties, such as density and the heat of vaporization. The same approach can be applied to more sophisticated water models that can better represent pure water properties. These results lend further support to concept of integrating host-guest binding data into force field parameterization.

show abstract

Toward Expanded Diversity of Host-Guest Interactions via Synthesis and Characterization of Cyclodextrin Derivatives

Cited by 6 publications

References 40 publications

Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software

Bind3P: Optimization of a Water Model with Host-Guest Binding Data

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