Simulation optimization of spherical non-polar guest recognition by deep-cavity cavitands

Abstract

Biomimetic deep-cavity cavitand hosts possess unique recognition and encapsulation properties that make them capable of selectively binding a range of non-polar guests within their hydrophobic pocket. Adamantane based derivatives which snuggly fit within the pocket of octa-acid deep cavity cavitands exhibit some of the strongest host binding. Here we explore the roles of guest size and attractiveness on optimizing guest binding to form 1:1 complexes with octa-acid cavitands in water. Specifically we simulate the water-mediated interactions of the cavitand with adamantane and a range of simple Lennard-Jones guests of varying diameter and attractive well-depth. Initial simulations performed with methane indicate hydrated methanes preferentially reside within the host pocket, although these guests frequently trade places with water and other methanes in bulk solution. The interaction strength of hydrophobic guests increases with increasing size from sizes slightly smaller than methane to Lennard-Jones guests comparable in size to adamantane. Over this guest size range the preferential guest binding location migrates from the bottom of the host pocket upwards. For guests larger than adamantane, however, binding becomes less favorable as the minimum in the potential-of-mean force shifts to the cavitand face around the portal. For a fixed guest diameter, the Lennard-Jones well-depth is found to systematically shift the guest-host potential-of-mean force to lower free energies, however, the optimal guest size is found to be insensitive to increasing well-depth. Ultimately our simulations show that adamantane lies within the optimal range of guest sizes with significant attractive interactions to match the most tightly bound Lennard-Jones guests studied.

Molecular Dynamics Simulations of Water‐Mediated Cholesterol Capture within an Open‐Ended Single‐Walled Carbon Nanotube

“…The repulsive role of water in such host‐guest association has been previously observed for the confinement of non‐polar guests within CNT and cavitands hosts in water. Similarly, one of the investigations has shown that water contributes unfavorably in the aggregation of large pseudo‐spherical non‐polar solute pairs such as bicyclooctane, adamantane and fullerene .…”

Xe affinities of water-soluble cryptophanes and the role of confined water

“…Water molecules in many binding sites must necessarily be displaced to accommodate the binding of a guest species. 27 The work required for such displacement is a component of the free energy of binding, and this component is expected to increase (lower binding affinity) with increasing numbers of water molecules to be displaced. For hydrophobic host cavities, this process is often accompanied by an entropy gain due to the release of the ordered water molecules sequestered inside a confined host environment into the bulk solvent.…”

Principles for Tuning Hydrophobic Ligand–Receptor Binding Kinetics

“…A variety of phenomena exemplify the wide momentousness of hydrophobicity in natural, engineering and pharmaceutical sciences, such as self-assembly of amphiphilic molecules to biological membranes [7,46], molecular recognition [9,[47][48][49][50][51][52][53][54][55][56][57][58], catalysis using cavitands [59][60][61][62], transport through nano-pores [63][64][65], as well as protein folding, stability, and function [66][67][68][69]. The work here especially focuses on how capillary evaporation rates influence the association kinetics of small hydrophobic ligands to hemispherically molded hydrophobic binding sites.…”

“…Also, receptors in cell membranes are activated if their binding pockets take up a small molecule, such as a neurotransmitter [73], a hormone [74], or a pharmaceutical drug [75]. Moreover, chemical engineers copy this binding principle from nature for supramolecular chemistry, where so-called cavitands [59,62,76] or macrocycles [77] are designed as molecular containers. The underlying principle is often compared to a "lock" and "key", or a "host" and "guest", whereas the binding agent serves as the "key" or "guest" that selectively fits into the concavely shaped "lock" or "host".…”

“…In sum, the influence of hydrophobicity on binding affinity is tunable due to chemical and topographical modifications of the binding partners [58,[90][91][92][93][94][95]. With that in mind, especially synthetic key-lock systems, i.e., cavitands, proved to be amenable and adaptable to hands-on, guided mutations [61,62].…”