Unraveling the relationship between R343C vitamin D receptor polymorphism and vitamin D deficiency in the progression of mild cognitive impairment to dementia: a in silico study

Low vitamin D concentrations are related to cognitive impairment and dementia. On this account, a molecular modeling study was used to identify the association between vitamin D receptor polymorphism and vitamin D deficiency. The single nucleotide polymorphism analysis using Meta-Single Nucleotide Polymorphism, I-Mutant v2.0, Mupro, and DUET reveals vitamin D receptor R343C (rs1057521095), R391C (rs121909800) and R391H (rs776088779) as the crucial disease-causing and destabilizing mutants. The molecular docking study using AutoDock exposed the high binding energy of calcitriol with wild vitamin D receptor (−11.61 kcal/mol) than the mutants vitamin D receptor R343C (−8.3 kcal/mol), R391C (−9.5 kcal/mol) and R391H (−10.2 kcal/mol). The weakly binding vitamin D receptor R343C was subjected to 200 ns molecular dynamics simulations and the trajectory analysis reveals the greater stability of the wild vitamin D receptor-calcitriol complex than the mutant vitamin D receptor R343C-calcitriol complex. Overall, the R343C mutation causes conformational changes and reduces the binding affinity of calcitriol with the vitamin D receptor, which may lead to vitamin D deficiency and increase the risk of dementia.