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

Abstract

Pain is a global health burden requiring effective therapeutic strategies. Gabapentin (GBP) and pregabalin (PGB), used for neuropathic pain, act primarily through alpha2delta subunits of voltage-gated calcium channels. Caenorhabditis elegans expresses UNC-36, an ortholog of mammalian alpha2delta proteins involved in calcium-channel function and nocifensive behavior. However, whether UNC-36 retains the features essential for gabapentinoid recognition remains unclear. We compared human alpha2delta-1 and UNC-36 using sequence and structural analyses, docking, one 500-ns molecular dynamics trajectory per complex, distance-based contact profiling, principal component and free-energy landscape analyses, and MM/GBSA calculations. The modeled proteins showed C-alpha correspondence within a selected 13-residue pocket core (RMSD 0.53 Angstrom), whereas the complete 14-residue mapping yielded 9.07 Angstrom. All four trajectories showed recurrent ligand-protein proximity contacts with residue-level patterns. Aromatic-residue contacts accounted for a larger fraction of contact records in human trajectories, whereas basic-residue proximity was more frequent in UNC-36 trajectories, including recurrent Arg501 and Arg503 contacts. Human alpha2delta-1/PGB showed the lowest ligand RMSD, while alpha2delta-1/GBP showed greater positional variation. In UNC-36, PGB deviated more from its initial pose than GBP. The first two principal components accounted for more conformational variance in UNC-36 complexes than in human complexes. MM/GBSA estimates, without an explicit conformational-entropy contribution, were more negative for PGB than GBP in human trajectories and for GBP than PGB in UNC-36 trajectories. These simulations suggest that selected pocket-core correspondence coexists with differences in modeled contacts, sampled motions, and estimates. They provide hypotheses for investigating gabapentinoid recognition by UNC-36 and its pharmacological relevance.

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