Comparative Molecular Dynamics Analysis of Dopamine Receptors in C. elegans and Human Reveal Common Domains and Ligand Interactions with Implications for Parkinson’s Disease

Parkinson's disease imposes substantial health and economic burdens worldwide, underscoring the need for efficient model systems to study dopaminergic signaling and L-DOPA pharmacology.This study examines dopamine receptor structure and interaction behavior in Caenorhabditis elegans and humans to assess cross-species conservation at the molecular level.Despite their evolutionary distance, human and C. elegans dopamine receptors exhibited strong convergence in interaction architecture and conformational responses.By integrating molecular docking, molecular dynamics simulations, interaction fingerprinting, and conformational landscape analysis, we identified conserved catecholamine recognition frameworks across D1-and D2-type receptors despite approximately 600 million years of divergence.Dopamine and L-DOPA engaged homologous receptor regions in both species, adopting comparable interaction poses.Molecular dynamics simulations demonstrated stable ligand-receptor engagement and preserved receptor architecture over 100-ns trajectories.Principal component analysis and Free Energy Landscapes (FEL) showed more confined conformational sampling for dopamine compared to L-DOPA.Conserved interaction networks involved TM3 ionic anchoring, TM5 serine microdomains coordinating catechol groups, and expanded aromatic interaction motifs in C. elegans receptors.Together, these findings establish C. elegans as a structurally and mechanistically relevant model for studying dopaminergic signaling and provide an interaction-level framework for interpreting L-DOPA-associated receptor dynamics relevant to Parkinson's disease.