Structural conservation of the gabapentinoid binding site in human and Caenorhabditis elegans α2δ subunits: a docking and molecular dynamics perspective

In human alpha2delta-1 versus Caenorhabditis elegans UNC-36, a 13-residue pocket core is structurally conserved (RMSD 0.53 Angstrom), but ligand contacts and dynamics differ.

• Why it matters: Gabapentin and pregabalin act on alpha2delta subunits, yet it is unclear whether the C. elegans UNC-36 ortholog preserves the features needed for gabapentinoid recognition.
• What they did: The authors compared human alpha2delta-1 and UNC-36 with sequence/structure analyses, docking, one 500-ns molecular dynamics trajectory per complex, contact profiling, principal component and free-energy landscape analyses, and MM/GBSA calculations.
• The result: Across trajectories, recurrent proximity contacts differed by species and ligand (e.g., aromatic contacts more in human; basic-residue proximity more in UNC-36, including Arg501 and Arg503), and MM/GBSA favored PGB over GBP in human but GBP over PGB in UNC-36.

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