Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations

Molecular dynamics simulation techniques have been used to study the unbinding pathways of 1alpha,25-dihydroxyvitamin D(3) from the ligand-binding pocket of the vitamin D receptor (VDR). The pathways observed in a large number of relatively short (< 200 ps) random acceleration molecular dynamics (RAMD) trajectories were found to be in fair agreement, both in terms of pathway locations and deduced relative preferences, compared to targeted molecular dynamics (TMD) and streered molecular dynamics simulations (SMD). However, the high-velocity ligand expulsions of RAMD tend to favor straight expulsion trajectories and the observed relative frequencies of different pathways were biased towards the probability of entering a particular exit channel. Simulations indicated that for VDR the unbinding pathway between the H1-H2 loop and the beta-sheet between H5 and H6 is more favorable than the pathway located between the H1-H2 loop and H3. The latter pathway has been suggested to be the most likely unbinding path for thyroid hormone receptors (TRs) and a likely path for retinoic acid receptor. Ligand entry/exit through these two pathways would not require displacement of H12 from its agonistic position. Differences in the packing of the H1, H2, H3 and beta-sheet region explain the changed relative preference of the two unbinding pathways in VDR and TRs. Based on the crystal structures of the ligand binding domains of class 2 nuclear receptors, whose members are VDR and TRs, this receptor class can be divided in two groups according to the packing of the H1, H2, H3 and beta-sheet region.