Binding pathways of ligands to HIV-1 protease: Coarse-grained and atomistic simulations

Multiscale simulations (coarse-grained Brownian dynamics simulations and all-atom molecular dynamics simulations in implicit solvent) were applied to reveal the binding processes of ligands as they enter the binding site of the HIV-1 protease. The initial structures used for the molecular dynamics simulations were generated based on the Brownian dynamics trajectories, and this is the first molecular dynamics simulation of modeling the association of a ligand with the protease. We found that a protease substrate successfully binds to the protein when the flaps are fully open. Surprisingly, a smaller cyclic urea inhibitor (XK263) can reach the binding site when the flaps are not fully open. However, if the flaps are nearly closed, the inhibitor must rearrange or binding can fail because the inhibitor cannot attain proper conformations to enter the binding site. Both the peptide substrate and XK263 can also affect the protein's internal motion, which may help the flaps to open. Simulations allow us to efficiently study the ligand binding processes and may help those who study drug discovery to find optimal association pathways and to design those ligands with the best binding kinetics.