How neocarcerand Octacid4 self-assembles with guests into irreversible noncovalent complexes and what accelerates the assembly

Abstract

Cram's supramolecular capsule Octacid4 can irreversibly and noncovalently self-assemble with small-molecule guests at room temperature, but how they self-assemble and what accelerates their assembly remain poorly understood. This article reports 81 distinct Octacid4•guest self-assembly pathways captured in unrestricted, unbiased molecular dynamics simulations. These pathways reveal that the self-assembly was initiated by the guest interaction with the cavity portal exterior of Octacid4 to increase the portal collisions that led to the portal expansion for guest ingress, and completed by the portal contraction caused by the guest docking inside the cavity to impede guest egress. The pathways also reveal that the self-assembly was accelerated by engaging populated host and guest conformations for the exterior interaction to increase the portal collision frequency. These revelations may help explain why the presence of an exterior binding site at the rim of the enzyme active site is a fundamental feature of fast enzymes such as acetylcholinesterase and why small molecules adopt local minimum conformations when binding to proteins. Further, these revelations suggest that irreversible noncovalent complexes with fast assembly rates could be developed-by engaging populated host and guest conformations for the exterior interactions-for materials technology, data storage and processing, molecular sensing and tagging, and drug therapy.

Fig. 1. Structure of Octacid4 in complex with a small-molecule guest.

a Octacid4•p-xylene. b Octacid4•naphthalene. c Octacid4•1,4-dioxane. Carbon and oxygen are in blue and red, respectively. The axial or equatorial portal of Octacid4 comprises the C3 and C19 atoms or the O7, O15, C6b, and C17a atoms, respectively. Hydrogen and counter ion are not displayed for clarity.

Fig. 2. Three common steps of the 40 Octacid4•p-xylene self-assembly pathways at 298 K.

Octacid4 and p-xylene are in the stick and stick-and-ball models, respectively. Carbon and oxygen are in orange and red, respectively. Hydrogen, counter ion, and the p-xylenes in the bulk phase are not displayed for clarity. The noncovalent interaction gradient isosurfaces show the intermolecular interactions using a blue–red scale with blue indicating strong attractions and red indicating strong repulsions. All conformations shown here were obtained directly (no energy minimization) from Simulation 19 of the 40 14,251.6-ns simulations at 298 K. The isosurfaces show no repulsion but increasing attraction between the two molecules throughout the pathway.

Fig. 3. Three common steps of the 26 Octacid4•1,4-dioxane self-assembly pathways at 298 and 340 K.

Octacid4 and 1,4-dioxane are in the stick and stick-and-ball models, respectively. Carbon, oxygen, and sodium are in orange, red, and purple, respectively. Hydrogen, counter ion, and the 1,4-dioxanes in the bulk phase are not displayed for clarity, except for the ion that chelates 1,4-dioxane. The noncovalent interaction gradient isosurfaces show the intermolecular interactions using a blue–red scale with blue indicating strong attractions and red indicating strong repulsions. All conformations shown here were obtained directly (no energy minimization) from Simulation 76 of the 100 6320-ns simulations at 298 K. The isosurfaces reveal no repulsion but increasing attraction between the two molecules throughout the pathway.

Fig. 4. Three common steps of the 15 Octacid4•naphthalene self-assembly pathways at 298, 340, and 363 K.

Octacid4 and naphthalene are in the stick and stick-and-ball models, respectively. Carbon and oxygen are in orange and red, respectively. Hydrogen, counter ion, and the naphthalene in the bulk phase are not displayed for clarity. The noncovalent interaction gradient isosurfaces show the intermolecular interactions using a blue–red scale with blue indicating strong attractions and red indicating strong repulsions. All conformations shown here were obtained directly (no energy minimization) from Simulation 34 of the 100 6320-ns simulations at 298 K. The isosurfaces reveal no major repulsion but increasing attraction between the two molecules throughout the pathway.

Fig. 5. Noncovalent interaction gradient isosurfaces of 1,4-dioxane in different conformations.

a The chair conformation. b The half-chair conformation. Carbon and oxygen are in green and red, respectively. Hydrogen is not displayed for clarity. The gradient isosurfaces show the intramolecular interactions using a blue–red scale with blue indicating strong attractions and red indicating strong repulsions. All conformations shown here were obtained directly (no energy minimization) from Simulation 30 of the 100 6320-ns simulations at 298 K. The isosurfaces in panels a and b show stronger intramolecular repulsion in the half-chair conformation than that of the chair conformation.

Fig. 6. Three conformational clusters of the 40 Octacid4•p-xylene self-assembly pathways at 298 K.

a The most-populated cluster with two nearly orthogonal linkers that strongly attract p-xylene. b The less-populated cluster with two nearly parallel linkers that moderately attract p-xylene. c The least-populated cluster with two nearly-coplanar linkers that weakly attract p-xylene. The noncovalent interaction gradient isosurfaces show the intermolecular interactions using a blue–red scale with blue indicating strong attractions and red indicating strong repulsions. All conformations shown here were obtained directly (no energy minimization) from Simulations 17 for a, 7 for b, and 36 for c of the 40 14,251.6-ns simulations at 298 K.

Fig. 7. Sodium-restrained Octacid4 conformations.

a One pair of linkers that form bidendate coordination with the sodium cation. b Two pairs of linkers that form bidendate coordination with the sodium cation. Left: side view; Right: top view.

Fig. 8. The exponential decay of the host population over the simulation time for the Octacid4•p-xylene self-assembly at 298 K.

The host population and simulation time were obtained from the 40 individual complexation times of p-xylene listed in Table S2. The linear-regression analysis was performed using the PRISM 5 program.