Authors: Diane Uwacu, Everett Yang, Shawna Thomas, Nancy M. Amato

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Abstract:
Despite many efforts and considerable breakthroughs in ligand binding prediction, the best predictors still produce many false positives and a reliable, fully automated prediction framework has yet to be developed. Binding site accessibility is an important feature ignored by methods that classify binding based solely on the energetic or geometric properties of the final bound protein-ligand complex. To evaluate this necessity, we transform the ligand accessibility problem into a robot motion planning problem where the ligand is modeled as a flexible agent whose task is to travel from outside the protein to its binding site. We use Rapidly-exploring Random Graphs coupled with Mean Curve workspace skeletons to quickly and thoroughly explore a protein environment in order to produce valid paths for ligand motion. Path weights reflect the influences of intermolecular forces on the given ligand. Low weight paths are extracted and analyzed for characteristics of accessibility. In this paper, we show that our algorithm provides a mechanism to evaluate binding site accessibility for a ligand. 

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