Abstract
Molecular dynamics simulations of hemicarcerands and related variants allow the study of constrictive binding and offer insight into the rules of molecular complexation, but are limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. There have been no molecular dynamics simulations of the reported water-soluble hemicarcerand (Octacid4) that explain how Octacid4 encapsulates guests at 298 K and keeps them encapsulated at 298 K in NMR experiments. Herein we report a modular approach to hemicarcerand simulations that simplifies the model building and charge derivation in a manner reminiscent of the approach to protein simulations with truncated amino acids as building blocks. We also report that in aqueous molecular dynamics simulations at 298 K apo Octacid4 adopts two clusters of conformations one of which has an equatorial portal open but the guest-bound Octacid4 adopts one cluster of conformations with all portals closed. These results explain how Octacid4 incarcerates guests at room temperature and suggest that the guest-induced host conformational change that impedes decomplexation is a previously unrecognized conformational characteristic that promotes strong molecular complexation.
Highlights
Molecular dynamics simulations of hemicarcerands and related variants allow the study of constrictive binding and offer insight into the rules of molecular complexation, but are limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive
Because of the need to balance the atomic charges of the water-soluble hemicarcerand with the charges of the aqueous solvent and the charges of the small-molecule guest when using an AMBER forcefield such as FF12MClm[16], the hemicarcerand charges need to be derived from ab initio calculations using the HF/6-31G* basis set that uniformly overestimates the polarity of the molecule
This is because (1) aqueous solvent models include polarization effects due to the empirical calibration to reproduce the density and enthalpy of liquid vaporization[17], and (2) the small-molecule guest bears the restrained electrostatic potential (RESP) charges that are derived from ab initio calculations using the HF/6-31G* basis set[18,19,20]
Summary
Molecular dynamics simulations of hemicarcerands and related variants allow the study of constrictive binding and offer insight into the rules of molecular complexation, but are limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. Variations of the torsions of the four Octacid[4] linkers can result in many distinct conformations, which complicates the derivation of the conformation-dependent atomic charges of Octacid[4] These technical complexities, as detailed below, may explain why there have hitherto been no aqueous MD simulations of Octacid[4] to understand how it unusually encapsulates various small-molecule guests at 298 K and keeps them encapsulated at the same temperature such that the bound guests can be differentiated in their NMR spectra from those in the bulk phase[7]. We report the characterization of the host cavity and the guest motion inside the host in the MD simulations using the modular method This characterization explains how Octacid[4] incarcerates guests in a manner fundamentally different from those of carcerands and hemicarcerands, and offers mechanistic insight into molecular complexation
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