English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

The theory of receptor-ligand binding equilibria has long beenwell-established in biochemistry, and was primarily constructed to describedilute aqueous solutions. Accordingly, few computational approaches have beendeveloped for making quantitative predictions of binding probabilities inenvironments other than dilute isotropic solution. Existing techniques, rangingfrom simple automated docking procedures to sophisticated thermodynamics-basedmethods, have been developed with soluble proteins in mind. Biologically andpharmacologically relevant protein-ligand interactions often occur in complexenvironments, including lamellar phases like membranes and crowded, non-dilutesolutions. Here we revisit the theoretical bases of ligand binding equilibria,avoiding overly specific assumptions that are nearly always made whendescribing receptor-ligand binding. Building on this formalism, we extend theasymptotically exact Alchemical Free Energy Perturbation technique toquantifying occupancies of sites on proteins in a complex bulk, includingphase-separated, anisotropic, or non-dilute solutions, using athermodynamically consistent and easily generalized approach that resolvesseveral ambiguities of current frameworks. To incorporate the complex bulkwithout overcomplicating the overall thermodynamic cycle, we simplify thecommon approach for ligand restraints by using a singledistance-from-bound-configuration (DBC) ligand restraint during AFEP decouplingfrom protein. DBC restraints should be generalizable to binding modes of mostsmall molecules, even those with strong orientational dependence. We apply thisapproach to compute the likelihood that membrane cholesterol binds to knowncrystallographic sites on 3 GPCRs at a range of concentrations. Non-ideality ofcholesterol in a binary cholesterol:POPC bilayer is characterized andconsistently incorporated into the interpretation.

A streamlined, general approach for computing ligand binding free energies and its application to GPCR-bound cholesterol