Regulating the conformation of prion protein through ligand binding.

Although some antiprion compounds have been shown to interfere with the pathological conversion of prion protein into a misfolded isoform, the actual mechanism has not been elucidated. In this study, we compared different conformations of prion protein with and without ligand binding, based on molecular dynamics simulations, to clarify the role of a typical antiprion compound termed GN8. In our approach, urea-driven unfolding simulations were employed to assay whether or not GN8 prevents denaturation of prion protein. We found that urea mediates partial unfolding at helix B of the prion protein, suggesting a transition into the intermediate states of the pathological conversion. However, GN8 efficiently suppressed local fluctuations by binding to flexible spots on helix B and prevented its urea-induced denaturation. We conclude that GN8 inhibits pathological conversion by suppressing the level of the intermediate. This is the first evidence supporting the chemical chaperone hypothesis, which states that GN8 acts as a chaperone to stabilize the normal form of the prion protein. Our basic principle constitutes a promising strategy for a dynamics-based drug design of therapeutic compounds, particularly for prion diseases and other diseases related to protein misfolding.