The association of ligand and protein is of fundamental importance in biology and chemistry. Although diffusion-control one-step association processes are well studied, many binding events have multiple steps and are also affected by more complicated interactions. We have developed and applied computational tools to study these multi-step ligand-protein associations that combine Brownian dynamics (BD) with coarse-grained model and atomistic MD simulations. The study uses HIV-1 protease as a model system. Our BD simulations show that the structural adjustment of the ligand toward its final stable state is the limiting step in the binding processes, which is highly system dependent. We therefore used atomistic MD simulations to study detailed intermolecular attraction during the association processes. The results highlight broad implications in recognition pathways under complex environment that considers molecular dynamics, conformational changes and waters. This work brings insights into ligand�protein associations and is helpful in the design of targeted ligands.

Modeling ligand-protein association: Diffusing, gating, and intermolecular interactions

243rd National Meeting (2012)

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