Dataset Information

Thermodynamic Contribution of Water in Cryptophane Host-Guest Binding Reaction.

ABSTRACT: A detailed examination of binding thermodynamics is undertaken for the interaction between rubidium ion and a water-soluble cryptophane molecule using isothermal titration calorimetry. The equilibrium-binding quotient for this host-guest pair decreases with increasing product formation. When analyzed with a thermodynamic framework that considers water explicitly in the governing equation, the shift in equilibrium is ascribed to an unfavorable change in the free energy of solvation upon formation of the inclusion complex. A van't Hoff analysis of the binding data, as well as an observation of aggregation between inclusion complexes, suggests that charge-charge interactions between rubidium ion and the phenolate groups of the cryptophane host provide the driving force for association in water that overcomes a large and unfavorable change in solvent enthalpy.

SUBMITTER: Eggers DK

PROVIDER: S-EPMC10479154 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Thermodynamic Contribution of Water in Cryptophane Host-Guest Binding Reaction.

Eggers Daryl K DK Fu Sherry S Ngo Dominic V DV Vuong Elizabeth H EH Brotin Thierry T

The journal of physical chemistry. B 20200717 30

A detailed examination of binding thermodynamics is undertaken for the interaction between rubidium ion and a water-soluble cryptophane molecule using isothermal titration calorimetry. The equilibrium-binding quotient for this host-guest pair decreases with increasing product formation. When analyzed with a thermodynamic framework that considers water explicitly in the governing equation, the shift in equilibrium is ascribed to an unfavorable change in the free energy of solvation upon formation ...[more]

PMID: 32614599

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Project description:Computational prediction of noncovalent binding free energies with methods based on molecular mechanical force fields has become increasingly routine in drug discovery projects, where they promise to speed the discovery of small molecule ligands to bind targeted proteins with high affinity. Because the reliability of free energy methods still has significant room for improvement, new force fields, or modifications of existing ones, are regularly introduced with the aim of improving the accuracy of molecular simulations. However, comparatively little work has been done to systematically assess how well force fields perform, particularly in relation to the calculation of binding affinities. Hardware advances have made these calculations feasible, but comprehensive force field assessments for protein-ligand sized systems still remain costly. Here, we turn to cyclodextrin host-guest systems, which feature many hallmarks of protein-ligand binding interactions but are generally much more tractable due to their small size. We present absolute binding free energy and enthalpy calculations, using the attach-pull-release (APR) approach, on a set of 43 cyclodextrin-guest pairs for which experimental ITC data are available. The test set comprises both α- and β-cyclodextrin hosts binding a series of small organic guests, each with one of three functional groups: ammonium, alcohol, or carboxylate. Four water models are considered (TIP3P, TIP4Pew, SPC/E, and OPC), along with two partial charge assignment procedures (RESP and AM1-BCC) and two cyclodextrin host force fields. The results suggest a complex set of considerations when choosing a force field for biomolecular simulations. For example, some force field combinations clearly outperform others at the binding enthalpy calculations but not for the binding free energy. Additionally, a force field combination which we expected to be the worst performer gave the most accurate binding free energies - but the least accurate binding enthalpies. The results have implications for the development of improved force fields, and we propose this test set, and potential future elaborations of it, as a powerful validation suite to evaluate new force fields and help guide future force field development.

Project description:Software to more rapidly and accurately predict protein-ligand binding affinities is of high interest for early-stage drug discovery, and physics-based methods are among the most widely used technologies for this purpose. The accuracy of these methods depends critically on the accuracy of the potential functions that they use. Potential functions are typically trained against a combination of quantum chemical and experimental data. However, although binding affinities are among the most important quantities to predict, experimental binding affinities have not to date been integrated into the experimental data set used to train potential functions. In recent years, the use of host-guest complexes as simple and tractable models of binding thermodynamics has gained popularity due to their small size and simplicity, relative to protein-ligand systems. Host-guest complexes can also avoid ambiguities that arise in protein-ligand systems such as uncertain protonation states. Thus, experimental host-guest binding data are an appealing additional data type to integrate into the experimental data set used to optimize potential functions. Here, we report the extension of the Open Force Field Evaluator framework to enable the systematic calculation of host-guest binding free energies and their gradients with respect to force field parameters, coupled with the curation of 126 host-guest complexes with available experimental binding free energies. As an initial application of this novel infrastructure, we optimized generalized Born (GB) cavity radii for the OBC2 GB implicit solvent model against experimental data for 36 host-guest systems. This refitting led to a dramatic improvement in accuracy for both the training set and a separate test set with 90 additional host-guest systems. The optimized radii also showed encouraging transferability from host-guest systems to 59 protein-ligand systems. However, the new radii are significantly smaller than the baseline radii and lead to excessively favorable hydration free energies (HFEs). Thus, users of the OBC2 GB model currently may choose between GB cavity radii that yield more accurate binding affinities and GB cavity radii that yield more accurate HFEs. We suspect that achieving good accuracy on both will require more far-reaching adjustments to the GB model. We note that binding free-energy calculations using the OBC2 model in OpenMM gain about a 10× speedup relative to corresponding explicit solvent calculations, suggesting a future role for implicit solvent absolute binding free-energy (ABFE) calculations in virtual compound screening. This study proves the principle of using host-guest systems to train potential functions that are transferrable to protein-ligand systems and provides an infrastructure that enables a range of applications.

Dataset Information

Thermodynamic Contribution of Water in Cryptophane Host-Guest Binding Reaction.

Publications

Thermodynamic Contribution of Water in Cryptophane Host-Guest Binding Reaction.

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