Insights into prion protein function from atomistic simulations

Abstract

Computer simulations are a powerful tool for studies of biological systems. They have often been used to study prion protein (PrP), a protein responsible for neurodegenerative diseases, which include "mad cow disease" in cattle and Creutzfeldt-Jacob disease in humans. An important aspect of the prion protein is its interaction with copper ion, which is thought to be relevant for PrP's yet undetermined function and also potentially play a role in prion diseases. for studies of copper attachment to the prion protein, computer simulations have often been used to complement experimental data and to obtain binding structures of Cu-PrP complexes. This paper summarizes the results of recent ab initio calculations of copper-prion protein interactions focusing on the recently discovered concentration-dependent binding modes in the octarepeat region of this protein. In addition to determining the binding structures, computer simulations were also used to make predictions about PrP's function and the role of copper in prion diseases. The results demonstrate the predictive power and applicability of ab initio simulations for studies of metal-biomolecular complexes.

Figure 1

The binding site of the copper ion at high Cu concentration. Copper is shown in gold, oxygens are red, nitrogens blue, hydrogen white and carbons are cyan.

Figure 2

The structure of the low concentration copper binding site in the octarepeat domain of PrP.

Figure 3

The structure of the medium concentration copper binding mode in the octarepeat domain of PrP.

Figure 4

Structures of full-length prion protein in various copper binding modes. (A) Free PrP, (B) Low concentration mode, one copper ion coordinated by His61, His69, His77 and His85, (C) medium concentration mode: two copper ions are attached to His61, His69 and His77, His85, respectively, (D) High concentration mode: four copper ions are attached, each ion is anchored by one of the following: His61, His69, His77 and His85. The copper atoms are shown as gold spheres. The octarepeat domain is colored blue, the non-octarepeat region of the N-terminal is colored grey. The α-helices and β-sheet in C-terminal are displayed in red and mangenta, respectively.