Molecular Dynamics Simulations of Two Tandem Octarepeats from the Mammalian Prion Protein: Fully-Cu2+-bound and Metal-free Forms

¹ University of Calgary

^* To whom correspondence should be addressed. E-mail: vogel{at}ucalgary.ca.

Submitted on March 23, 2007
Revised on May 30, 2007
Accepted on 11 July 2007

	Abstract

Molecular dynamics simulations have been conducted on a model fragment (Ac-PHGGGWGQPHGGGW-NH₂) of the prion protein octarepeat domain, both in the Cu²⁺-bound and metal-free forms. The copper-bound models are based on the consensus structure of the core Cu²⁺-binding site of an individual octarepeat, relevant to the fully Cu²⁺-occupied prion protein octarepeat region. The model peptides contain Cu²⁺ bound through a His imidazole ring and two deprotonated amide N-atoms in the peptide backbone supplied by the following two Gly residues. Both the copper-bound and metal-free models have been simulated with the OPLS all-atom force field with the GROMACS molecular dynamics package. These simulations with two tandem copper-binding sites represent the minimum model necessary to observe potential structuring between the copper-binding sites in the octarepeat region. The GWGQ residues constitute a flexible linker region that predominantly adopts a turn, serving to bring adjacent His residues into close proximity. Stable structures which form demonstrate that the copper-bound octarepeat region allows the copper-coordinating sites to come into van der Waals contact, packing into particular orientations that stabilize the bend in the GWGQ linker region.

Key Words: DFT Modeling, OPLS parameter derivation, copper sensing, neuroprotection, protein folding