How the water-soluble hemicarcerand incarcerates guests at room temperature decoded with modular simulations

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.

Fig. 1. Chemical structures of hemicarcerands and Octacid4.

Hemicarcerands carry a hydrophobic linker X, whereas Octacid4 has a 4,6-dimethylisophthalic acid fragment as a di-anionic linker that makes Octacid4 water soluble and functionally different from hemicarcerands.

Fig. 2. Distinct conformations of Octacid4.

Distances shown by thin dashed lines to indicate the open or closed equatorial portal are in Angstroms. Oxygen atoms are in red. Carbon atoms are in lime, green cyan, limon, cyan, marine, or yellow orange. Hydrogen atoms, counter ions and water molecules are not displayed for clarity. a Energy-minimization–derived Octacid4 in vacuo with all equatorial portals closed. b Energy-minimization–derived Octacid4 in vacuo with all equatorial portals open. c The most populated Octacid4 conformation with all equatorial portals closed in the aqueous MD simulations. d The second most populated Octacid4 conformation with one equatorial portal open in the aqueous MD simulations. e An Octacid4 conformation with one equatorial portal open in the aqueous MD simulations. f Another Octacid4 conformation with equatorial portals open in the aqueous MD simulations.

Fig. 3. Chemical structures of HC1 and HCD1 and the assembly of HC1 into the octa-anionic Octacid4.

Thick lines indicate the bonds between main-chain atoms. Thin lines indicate the bonds between side-chain atoms or between a main-chain atom and a side-chain atom. Thin dashed lines and colored lines indicate the respective intra- and inter-residue bonds that are constructed with cross-links. The double bonds and net charges are not displayed for clarity.

Fig. 4. The atoms that confine the Octacid4 cavity.

All atoms that confine the cavity are shown with the sphere model. The names of the atoms in the HC1 residue that confine the cavity are C1, C2, C3, C4, C5, C6, C6a, O5, O6a, O7, C6b, C18a, C16, C17, C18, C19, C20, C16a, O15, O16a, O17, and C17a.

Fig. 5. Time series of radius of gyration of the Octacid4 cavity.

Each time series was derived from the first of 20 distinct and independent MD simulations at 298 K (see Fig. S1 for those from all 20 simulations at 298/340/363 K).

Fig. 6. The most populated conformations of Octacid4 and its complexes in the MD simulations at 298 K.

a Octacid4. b DMSO•Octacid4. c EtOAc•Octacid4. d DMA•Octacid4. e 1,4-Dioxane•Octacid4. f DEA•Octacid4. g p-Xylene•Octacid4. h Naphthalene•Octacid4. The representative and average conformations in the largest conformation cluster of a set of 20 MD simulations for each complex are shown in the left and right panels, respectively. No energy minimization was performed on these representative and average conformations. The sulfur, oxygen, nitrogen, and carbon atoms are in yellow, red, blue, and green, respectively. Hydrogen atoms, counter ions and water molecules are not displayed for clarity.

Fig. 7. Noncovalent interaction gradient isosurfaces of Octacid4 and its complexes.

a Octacid4. b DMSO•Octacid4. c EtOAc•Octacid4. d DMA•Octacid4. e 1,4-Dioxane•Octacid4. f DEA•Octacid4. g p-Xylene•Octacid4. h Naphthalene•Octacid4. The energy-minimized Octacid4 or its complex conformation as the initial conformation for a set of 20 MD simulations is shown on the left. The representative conformation in the largest conformation cluster of the 20 MD simulations at 298 K is shown on the right. No energy minimization was performed on these representative conformations. The sulfur, oxygen, nitrogen, and carbon atoms are in yellow, red, blue, and gray, respectively. Hydrogen atoms, counter ions, and water molecules are not displayed for clarity. The gradient isosurfaces show the intramolecular (for a) and intermolecular (for b–h) interactions using a blue-red scale with blue indicating strong attractions and red indicating strong repulsions.