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

Understanding the underlying physics of the binding of small-molecule ligands to protein active sites is a key objective of computational chemistry and biology. It is widely believed that displacement of water molecules from the active site by the ligand is a principal (if not the dominant) source of binding free energy. Although continuum theories of hydration are routinely used to describe the contributions of the solvent to the binding affinity of the complex, it is still an unsettled question as to whether or not these continuum solvation theories describe the underlying molecular physics with sufficient accuracy to reliably rank the binding affinities of a set of ligands for a given protein. Here we develop a novel, computationally efficient descriptor of the contribution of the solvent to the binding free energy of a small molecule and its associated receptor that captures the effects of the ligand displacing the solvent from the protein active site with atomic detail. This descriptor quantitatively predicts (R(2) = 0.81) the binding free energy differences between congeneric ligand pairs for the test system factor Xa, elucidates physical properties of the active-site solvent that appear to be missing in most continuum theories of hydration, and identifies several features of the hydration of the factor Xa active site relevant to the structure-activity relationship of its inhibitors.

Role of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand Binding