Most biological processes are initiated or mediated by the association of ligands and proteins. This work studies multistep, ligand-protein association processes by Brownian dynamics simulations with coarse-grained models for HIV-1 protease (HIVp) and its neutral ligands. We report the average association times when the ligand concentration is 100 μM. The influence of crowding on the simulated binding time was also studied. HIVp has flexible loops that serve as a gate during the ligand binding processes. It is believed that the flaps are partially closed most of the time in its free state. To accelerate our simulations, we fixed a part of the HIVp and reparameterized our coarse-grained model, using atomistic molecular dynamics simulations, to reproduce the "gating" motions of HIVp. HIVp-ligand interactions changed the gating behavior of HIVp and helped ligands diffuse on HIVp surface to accelerate binding. The structural adjustment of the ligand toward its final stable state was the limiting step in the binding processes, which is highly system dependent. The intermolecular attraction between the ligands and crowder proteins contributes the most to the crowding effects. The results highlight broader implications in recognition pathways under more complex environment that considers molecular dynamics and conformational changes. This work brings insights into ligand-protein associations and is helpful in the design of targeted ligands.