Mapping the Ligand-dependent Remodeling of the Conformational Entropy Landscape in Neurotensin Receptor 1 by NMR-guided Molecular Simulations

This study presents a comprehensive analysis of the dynamic properties and allosteric regulation mechanisms of Class A G protein-coupled receptors (GPCRs) by integrating molecular dynamics (MD) simulations with nuclear magnetic resonance (NMR) relaxation measurements. Utilizing generalized order parameters derived from NMR data and MD trajectories, we quantitatively assess conformational entropy changes that occur during receptor activation and ligand binding events. This approach enables a detailed characterization of protein flexibility at multiple timescales, revealing how dynamic fluctuations contribute to allosteric signal transmission within the receptor. Our results demonstrate that conformational entropy plays a pivotal role in modulating the functional states of Class A GPCRs, influencing the equilibrium between inactive and active conformations. By elucidating the interplay between structural dynamics and allostery, this work advances the molecular-level understanding of GPCR function and highlights the importance of entropy-driven effects in receptor signaling. The integrative methodology and findings provide a valuable framework for future investigations aimed at targeting receptor dynamics in drug discovery and rational design of allosteric modulators.