On the Nature of Guest Complexation in Water: Triggered Wetting-Water-Mediated Binding.

The complexity of macromolecular surfaces means that there are still many open questions regarding how specific areas are solvated and how this might affect the complexation of guests. Contributing to the identification and classification of the different possible mechanisms of complexation events in aqueous solution, and as part of the recent SAMPL8 exercise, we report here on the synthesis and conformational properties of TEEtOA 2, a cavitand with conformationally flexible ethyl groups at its portal. Using a combination of ITC and NMR spectroscopy, we report the binding affinities of a series of carboxylates to 2 and compare it to a related cavitand TEMOA 1. Additionally, we report MD simulations revealing how the wetting of the pocket of 2 is controlled by the conformation of its rim ethyl groups and, correspondingly, a novel triggered wetting, guest complexation mechanism, whereby the approaching guest opens up the pocket of the host, inducing its wetting and ultimately allows the formation of a hydrated host-guest complex (H·G·H2O). A general classification of complexation mechanisms is also suggested.

Proximal charge effects on guest binding to a non-polar pocket.

Science still does not have the ability to accurately predict the affinity that ligands have for proteins. In an attempt to address this, the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) series of blind predictive challenges is a community-wide exercise aimed at advancing computational techniques as standard predictive tools in rational drug design. In each cycle, a range of biologically relevant systems of different levels of complexity are selected to test the latest modeling methods. As part of this on-going exercise, and as a step towards understanding the important factors in context dependent guest binding, we challenged the computational community to determine the affinity of a series of negatively and positively charged guests to two constitutionally isomeric cavitand hosts: octa-acid 1, and exo-octa acid 2. Our affinity determinations, combined with molecular dynamics simulations, reveal asymmetries in affinities between host-guest pairs that cannot alone be explained by simple coulombic interactions, but also point to the importance of host-water interactions. Our work reveals the key facets of molecular recognition in water, emphasizes where improvements need to be made in modelling, and shed light on the complex problem of ligand-protein binding in the aqueous realm.