title: Binding or Recognization of copper with prion protein: Knowledge from Cu-PHGGGWGQ Coordination Dynamics with Charge Transfer Model

Ke Chen (TALK)

Institution: Academy of Physics, Nanjing University


Author: Ke Chen, Jun Wang, Wenfei Li and Wei Wang

Affiliation: National Lab of Solid State Microstructure, Collaborative Innovation Center of Advanced Microstructures, and Department of Physics, Nanjing University, Nanjing 210093, China

Prion protein PrP takes an important role in neurodegenerative diseases. It is suggested that its binding between copper ions and the octapeptide(PHGGGWGQ)-repeat region in its N-terminus may modulate the local ionic environments and further facilitate amyloid aggregation. To understand the binding of copper ions with N-terminus of PrP is a step to understand the biological behaviors of PrP proteins. Besides, the competition between multiple copper-binding modes exemplifies the complexity of ion-peptide interaction. The copper-octapeptide interaction may act as a model system to study the recognition and binding processes between ion and peptides. In this work, we build up an effective copper-peptide force field based on quantum chemistry calculations. In our model, the effect of charge transfer, protonation/deprotonation and induced polarization are considered. With this force field, we successfully characterize the local geometry and complex interactions of the octapeptide around the copper ion. Furthermore, using enhanced sampling method as well as many unbinding dynamics simulations, the binding/unbinding processes of copper ion with an octapeptide are simulated throughly. Multiple binding pathways and the frequent dynamical exchange between ligands during copper binding with the octapeptide are observed. Among the binding sites, the backbone nitrogens are highly cooperative and serve as the core of binding site stability. We also determined a nonnative binding site, the backbone carbonyl oxygen of histidine, as an important intermediate in copper ion binding. The backbone oxygen of histidine breaks the cooperativity between backbone nitrogens by occupying the coordination site of neighboring nitrogen, and guides the binding pathway to bypass high free energy barrier, therefore helps copper binding. Additionally, the backbone oxygen can hardly substitute neighboring nitrogen once copper has fully coordinated, resulting a 'lock' mechanism that enhances stability of copper binding site. With all these results, the picture of copper-octapeptide binding is outlined. The cooperative stablization of neighboring backbone nitrogens and the intermediate state with the coordination between ions and the neighboring oxygen from N-terminal direction are likely to happen in all ion-peptide interactions, which may be a universal binding pathway, since it is an effective way to lower free energy barrier in dynamics. We believe that our studies is a valuable step to understand the complex ion-peptide binding processes.