Efficiently Differentiating Agonists and Competitive Antagonists for Weak Allosteric Protein–Ligand Interactions with Linear Response Theory

What makes an agonist and a competitive antagonist? In this work, we aim to answer this question by performing parallel tempering Monte Carlo simulations on the serotonin type 3A (5-HT3A) receptor. We use linear response theory to predict conformational changes in the 5-HT3A receptor active site after weak perturbations are applied to its allosteric binding sites. A covariance tensor is built from conformational sampling of its apo state, and a harmonic approximation allows us to substitute the calculation of ligand-induced forces with the binding site's displacement vector. Remarkably, our study demonstrates the feasibility of effectively discerning between agonists and competitive antagonists for multiple ligands, requiring computationally expensive calculations only once per protein.