Reproducibility Dataset for Antagonist-Bound GPCR Orthosteric Substate Analysis

Résumé fourni par la source

This repository contains the reproducibility dataset supporting the manuscript “Orthosteric Substates Reveal Distinct Hydration and Microswitch Geometries in Antagonist-Bound GPCRs.” The study examines three antagonist-bound class A GPCR systems: A2A–istradefylline, 5-HT2A–ketanserin, and 5-HT7–(R)-SB-269970. Each receptor–ligand complex was investigated using three independent 200-ns all-atom membrane molecular dynamics simulations, giving a total production sampling time of 1.8 μs. The archived dataset includes receptor–ligand starting structures and their provenance, retained CHARMM-GUI system-preparation and GROMACS simulation inputs, replica organization and workflow information, and processed trajectory-derived analysis data. The analysis data support receptor-fitted ligand clustering, replica-resolved cluster distributions, orthosteric anchor interactions, direct and water-mediated ligand–receptor interactions, hydration pathways, aromatic-contact and π-compatible geometry analyses, receptor microswitch descriptors, ligand-substate-conditioned receptor analysis, temporal sampling diagnostics, and analysis-window sensitivity assessments. Machine-readable data underlying Supplementary Tables S1–S11 are provided as CSV files. Additional frame-level source data are included for the 5-HT7–(R)-SB-269970 rep02 trajectory, including original GROMOS cluster assignments, Asp1653.32–ligand interaction descriptors, receptor microswitch measurements, and the 160–180 ns C1/C7 late-window sensitivity dataset. These files support the reported analysis of the late-emerging 5-HT7 C7 ligand substate and permit independent inspection of the underlying frame-resolved measurements. Trajectory-frame fractions and cluster occupancies in this dataset describe finite MD sampling and should not be interpreted as thermodynamic equilibrium populations. Continuous sampled segments are descriptive temporal-sampling measures rather than kinetic residence times, and ligand-substate-associated receptor microswitch geometries represent structural associations rather than evidence of receptor activation, pharmacological efficacy, or causal allosteric transitions. Complete production trajectory files are not included because of their large file size; the processed trajectory-derived datasets required to reproduce the quantitative results reported in the manuscript are included in this repository.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.