Publications

Although the non-covalent interactions between proteins and salts contributing to the Hofmeister effects have been generally mapped, there are many questions regarding the specifics of these interactions. We report here studies involving the small protein ubiquitin and salts of polarizable anions. These studies reveal a complex interplay between the reverse Hofmeister effect at low pH, the salting-in Hofmeister effect at higher pH, and six anion binding sites in ubiquitin at the root of these phenomena. These sites are all located at protuberances of preorganized secondary structure, and although stronger at low pH, are still apparent when ubiquitin possesses no net charge. These results demonstrate the traceability of these Hofmeister phenomena and suggest new strategies for understanding the supramolecular properties of proteins.

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.