Investigation of the metal binding octarepeat region from the human prion using nanoscale computer simulations
EMSL Project ID
25432
Abstract
Several debilitating neurodegenerative diseases, including mad cow and Creutzfeldt-Jakob diseases, are characterized by the production of a misfolded conformation of an endogenous cellular form of the prion protein. The misfolded "scrapie" prions, termed PrPSc, form protease-resistant aggregates, eventually leading to the formation of plaques within the central nervous system, similar to those found in Alzheimer's disease. The normal, healthy conformation of the cellular prion protein, PrPC, is a short-lived glycoprotein, and is found anchored to the outside membranes of many different cell types. Despite decades of searching, the exact biochemical mechanism of prion conversion and infection remains a mystery. One key area of prion research has focused on a highly conserved region of a repeated sequence of eight amino acids (PHGGGWGQ) located near the non-membrane bound N-terminus of the protein and is known to bind at least 4 copper (II) ions cooperatively. Protease binding and critical factors determining the amount of prion cellular uptake are likely focused in this region, making it very promising for therapeutic research. The atomistic binding modes of prion-copper complexes have been well studied by a variety of analytic techniques. Unfortunately, the larger macroscopic structure of the octarepeat region has remained elusive because the region behaves as a semi-random coil and is not easily resolved using crystallography. The goal of the proposed research will be to use molecular dynamics simulations to accurately characterize the dominant macroscopic structures of the octarepeat region. To achieve this goal, better polarizable and charge transfer models describing interactions with the copper (II) ion are required. Using the new potentials and a previously developed fluctuating charge methodology for the organic groups, we will carry out nanosecond timescale simulation of the fully solvated octarepeat region. The dominant folding and partially folded structures shall be characterized in an effort to better understand their biochemical significance. Comparisons will be made with experimental datasets and ongoing simple pairwise additive simulations of the same system.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-07-20
End Date
2008-07-29
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Yezdimer E, and RH Wood. 2010. "Problems with Some Current Water Models for Close Pair Interactions That Are Not Near the Minimum Energy." Journal of Chemical Theory and Computation 6(2):438-442. doi:10.1021/ct900447n