Structural dynamics of pathogenic ABCC8 single-nucleotide variants and their interactions with gliclazide

Pathogenic single-nucleotide variants (SNVs) in the ABCC8 gene have been associated with susceptibility to type 2 diabetes (T2D), and understanding how these variants alter protein structure is crucial for the development of personalized therapeutic strategies for T2D. Gliclazide binding to ABCC8 variants was assessed using molecular docking, 50 ns molecular dynamics simulation (MDS), and MM-PBSA. Docking indicated a conserved pose with affinity shifts; an Arg1144 hydrogen bond persisted in all variants, whereas the wild type (WT) engaged Tyr1293. More favorable docking energies coincided with π–π or π–sulfur contacts involving Trp1296 and Phe591/Tyr1293 or His584. Complexes remained stable during simulation, showing RMSD plateaus, stabilized radius of gyration and solvent-accessible surface area (SASA) after equilibration, and maintained ligand–receptor distances. Phe591Leu showed the most stable profile, whereas Asp1471Asn exhibited deviation. MM-PBSA predicted the strongest binding for the wild type (−21.86 ± 2.70 kcal/mol) and weaker, variant-dependent binding for mutants (−19.46 ± 3.33 to −16.34 ± 2.46 kcal/mol), supporting preserved binding. Experimental validation is required to investigate these variants in K ATP function and clinical response.