Molecular Dynamics Simulation Study on the Binding and Stabilization Mechanism of Antiprion Compounds to the “Hot Spot” Region of PrPC

Structural transitions in the prion protein from the cellular form, PrPC, into the pathological isoform, PrPSc, are regarded as the main cause of the transmissible spongiform encephalopathies, also known as prion diseases. Hence, discovering and designing effective antiprion drugs that can inhibit PrPC to PrPSc conversion is regarded as a promising way to cure prion disease. Among several strategies to inhibit PrPC to PrPSc conversion, stabilizing the native PrPC via specific binding is believed to be one of the valuable approaches and many antiprion compounds have been reported based on this strategy. However, the detailed mechanism to stabilize the native PrPC is still unknown. As such, to unravel the stabilizing mechanism of these compounds to PrPC is valuable for the further design and discovery of antiprion compounds. In this study, by molecular dynamics simulation method, we investigated the stabilizing mechanism of several antiprion compounds on PrPC that were previously reported to have specific binding to the "hot spot" region of PrPC. Our simulation results reveal that the stabilization mechanism of specific binding compounds can be summarized as (I) to stabilize both the flexible C-terminal of α2 and the hydrophobic core, such as BMD42-29 and GN8; (II) to stabilize the hydrophobic core, such as J1 and GJP49; (III) to stabilize the overall structure of PrPC by high binding affinity, as NPR-056. In addition, as indicated by the H-bond analysis and decomposition analysis of binding free energy, the residues N159 and Q160 play an important role in the specific binding of the studied compounds and all these compounds interact with PrPC in a similar way with the key interacting residues L130 in the β1 strand, P158, N159, Q160, etc. in the α1-β2 loop, and H187, T190, T191, etc. in the α2 C-terminus although the compounds have large structural difference. As a whole, our obtained results can provide some insights into the specific binding mechanism of main antiprion compounds to the "hot spot" region of PrPC at the molecular level and also provide guidance for effective antiprion drug design in the future.