The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations - Computational Modeling of Biological Systems - page 215

The Structure of Intrinsically Disordered
Peptides Implicated in Amyloid Diseases:
Insights from Fully Atomistic Simulations

Chun Wu and Joan-Emma Shea

1 Introduction

Protein aggregation involves the self-assembly of proteins into large “-sheet-rich
complexes. This process can be the result of aberrant protein folding and lead to
“amyloidosis,” a condition characterized by deposits of protein aggregates known
as amyloids on various organs of the body [ 1 ]. Amyloid-related diseases include,
among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease,
and type II diabetes [ 2 - 4 ]. In other instances, however, protein aggregation is not
a pathological process, but rather a functional one, with aggregates serving as
structural scaffolds in a number of organisms [ 5 ].
It is now well-established that the primary end-product of aggregation has a
fibril structure, with a cross-“-sheet pattern based on solid state nuclear magnetic
resonance (NMR), X-ray diffraction, electron microscope, and dye-binding studies
[ 6 - 9 ]. Despite the importance of the aggregation process from a biomedical perspec-
tive, several critical questions remain unanswered regarding the nature of the species
populated during the fibrillization process. The very starting point of aggregation—
the nature of the “misfolded” monomeric species—is unknown, particularly in the
case of large class of “intrinsically disordered” or “natively unfolded” proteins that
are prone to aggregation [ 10 , 11 ]. Rather than populating a well-defined three-
dimensional stable globular fold, these proteins interconvert among a number of
species. As a result, they are very difficult to characterize using traditional ensemble-
averaging methods such as NMR and circular dichroism (CD), although recent