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Buffer and Salt Effects in Aqueous Host-Guest Systems: Screening, Competitive Binding, or Both?

ABSTRACT: There are many open questions regarding the supramolecular properties of ions in water, a fact that has ramifications within any field of study involving buffered solutions. Indeed, as Pielak has noted (Buffers, Especially the Good Kind, Biochemistry, 2021, in press. DOI:10.1021/acs.biochem.1c00200) buffers were conceived of with little regard to their supramolecular properties. But there is a difficulty here; the mathematical models supramolecular chemists use for affinity determinations do not account for screening. As a result, there is uncertainty as to the magnitude of any screening effect and how this compares to competitive salt/buffer binding. Here we use a tetra-cation cavitand to compare halide affinities obtained using a traditional unscreened model and a screened (Debye-Hückel) model. The rule of thumb that emerges is that if ionic strength is changed by >1 order of magnitude─either during a titration or if a comparison is sought between two different buffered solutions─screening should be considered. We also build a competitive mathematical model showing that binding attenuation in buffer is largely due to competitive binding to the host by said buffer. For the system at hand, we find that the effect of competition is approximately twice that of the effect of screening (∼RT at 25 °C). Thus, for strong binders it is less important to account for screening than it is to account for competitive complexation, but for weaker binders both effects should be considered. We anticipate these results will help supramolecular chemists unravel the properties of buffers and so help guide studies of biomacromolecules.

SUBMITTER: Jordan JH

PROVIDER: S-EPMC8587612 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Buffer and Salt Effects in Aqueous Host-Guest Systems: Screening, Competitive Binding, or Both?

Jordan Jacobs H JH Ashbaugh Henry S HS Mague Joel T JT Gibb Bruce C BC

Journal of the American Chemical Society 20211027 44

There are many open questions regarding the supramolecular properties of ions in water, a fact that has ramifications within any field of study involving buffered solutions. Indeed, as Pielak has noted (Buffers, Especially the Good Kind, <i>Biochemistry</i>, <b>2021</b>, in press. DOI:10.1021/acs.biochem.1c00200) buffers were conceived of with little regard to their supramolecular properties. But there is a difficulty here; the mathematical models supramolecular chemists use for affinity determi ...[more]

PMID: 34704751

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Project description:Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small-molecule 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 druglike guest molecule 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.

Dataset Information

Buffer and Salt Effects in Aqueous Host-Guest Systems: Screening, Competitive Binding, or Both?

Publications

Buffer and Salt Effects in Aqueous Host-Guest Systems: Screening, Competitive Binding, or Both?

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