Docking Ligands on Protein Surfaces: The Case Study of Prion Protein.

Molecular docking of ligands targeting proteins undergoing fibrillization in neurodegenerative diseases is difficult because of the lack of deep binding sites. Here we extend standard docking methods with free energy simulations in explicit solvent to address this issue in the context of the prion protein surface. We focus on a specific ligand (2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide), which binds to the structured part of the protein as shown by NMR (Kuwata, K. et al. Proc Natl Acad Sci U.S.A. 2007, 104, 11921-11926). The calculated free energy of dissociation (7.8 ± 0.9 kcal/mol) is in good agreement with the value derived by the experimental dissociation constant (Kd = 3.9 μM, corresponding to ΔG(0) = -7.5 kcal/mol). Several binding poses are predicted, including the one reported previously. Our prediction is fully consistent with the presence of multiple binding sites, emerging from NMR measurements. Our molecular simulation-based approach emerges, therefore, as a useful tool to predict poses and affinities of ligand binding to protein surfaces.