This work studies multi-step, ligand-protein association processes by computer simulations. We selected HIV-1 protease and its inhibitors, xk623 and ritonavir, as our model system. To begin, we used Brownian dynamics (BD) simulations with coarse-grained models to study early stages of binding processes. Analysis of the BD trajectories guided detailed all-atom molecular dynamics simulations to study the structural adjustment of the ligand toward its final stable bound state. In our implicit MD simulation, both ligands can successfully bind to the active site. Our results show a stepwise switch of H-bond network and conformational arrangement. The slower kinetics can be attributed to multiple-step H-bond conversion and strong intramolecular H-bond. The distribution and large number of donor/acceptor atoms in the ligand slow down the binding kinetics due to formation of more complex forming intermediates. This work demonstrate general rules about the drug-receptor association mechanisms.

Pathways and mechanism of drugs binding to HIV-1 protease

246th National Meeting (2013)

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