Molecular recognition is a highly interdependent process. Subsite couplings within the active site are elicited through the optimization of substrates. Because the goal of substrate optimization and inhibition are in opposition, the present study examined the interdependency of the subsites of HIV-1 protease using a series of protease inhibitors. Previously, a series of DRV analogs carefully crafted to systematically probe the P1’ and P2’ subsites and co-crystallized structures provided the ideal data set to probe subsite interdependency. All-atom molecular dynamics simulations were performed and analyzed. Van der Waals contact energies, hydrophobic and electrostatic interactions and between the ligands and protease as well as water structures were examined. Comparison of chemical properties over the MD trajectories revealed that the P1’ subsite highly influences other subsites; affecting the van der Waals contacts in the P2’ subsite; hydrogen bond frequencies with catalytic residues and the flap water; and impacts the occupancy of conserved water sites both proximal and distal to the active site. Additionally, the effects of the inhibitor do not uniformly impact both monomers of HIV-1 protease. HIV-1 protease subsites are intricately linked. The relationships found here can be applied to new inhibitor designs and other potential therapeutic targets.

Interdependence of inhibitor recognition in HIV-1 protease subsites

253rd National Meeting (2017)

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