Differentiating Agonists and Competitive Antagonists of the Serotonin Type 3A (5-HT3A) Receptor

Abstract

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 applying weak perturbations 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 sites displacement vector. We show that it is possible to differentiate between agonists and competitive antagonists for multiple ligands while running computationally expensive calculations only once for the protein.