Unbinding of retinoic acid from the retinoic acid receptor by random expulsion molecular dynamics.
Unbinding pathways of retinoic acid (RA) bound to retinoic acid receptor (RAR) have been explored by the random expulsion molecular dynamics (REMD) method. Our results show that RA may exit the binding site of RAR through flexible regions close to the H1-H3 loop and beta-sheets, without displacing H12 from its agonist position. This result may explain kinetic differences between agonist and antagonist ligands observed for other nuclear receptors. The extended and flexible structure of RA initiated a methodological study in a simplified two-dimensional model system. The REMD force should in general be distributed to all atoms of the ligand to obtain the most unbiased results, but for a ligand which is tightly bound in the binding pocket through a strong electrostatic interaction, application of the REMD force on a single atom is preferred.
Carlsson
Peter
P
Department of Biosciences and Nutrition, Karolinska Institutet, and Karo Bio AB, Novum, SE-141 57 Huddinge, Sweden.
Burendahl
Sofia
S
Nilsson
Lennart
L
D001665:Binding Sites; D003198:Computer Simulation; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods; D011897:Random Allocation; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000648:ultrastructure*; D014212:Tretinoin / Q000737:chemistry*
D018168:Receptors, Retinoic Acid; D014212:Tretinoin