The theory of receptor–ligand binding equilibria has long been well-established in biochemistry, and was primarily constructed to describe dilute aqueous solutions. In contrast, biologically and pharmacologically relevant protein–ligand interactions often occur in complex environments, including lamellar phases like membranes. The plasma membrane comprises a highly heterogenous lipid solvent" that varies over time (due to modulation by the cell) and varies over space (due to lamellar structure, domain formation within the membrane, and lipid sorting by transmembrane proteins). Traditional formalisms for receptor-ligand binding employ overly specific assumptions that are violated within this environment. These assumptions also make interpretation of calculated binding free energies more difficult. I will present a more generalized framework for predicting site occupancies at an arbitrary ligand concentration that discards and/or circumvents these assumptions.<br/><br/>Our theoretical framework separates ligand-solvent interactions from ligand-receptor interactions and treats both sets of interactions with equivalent rigor. Consequently, existing microscopic models for complex liquid mixtures (in the absence of protein) can be consistently incorporated. When combined with Alchemical Free Energy Perturbation calculations or other methods that decompose binding processes into separate legs of the thermodynamics cycle, this approach allows for an efficient and powerful prediction of dose-response across a range of concentrations. As an example, I will present occupancy predictions for cholesterol binding sites on various GPCRs, over a range of concentrations. These calculations used a fraction of the computational cost required by a physical pathway method like umbrella sampling. For lower-affinity sites, the non-ideality of cholesterol in the membrane introduces detectable and surprising signatures into the binding curve.

Far from ideal: Specific binding in lipid phases

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.