The role of the acidic domain of α-synuclein in amyloid fibril formation: a molecular dynamics study.

The detailed mechanism of the pathology of α-synuclein in the Parkinson's disease has not been clearly elucidated. Recent studies suggested a possible chaperone-like role of the acidic C-terminal region of α-synuclein in the formation of amyloid fibrils. It was also previously demonstrated that the α-synuclein amyloid fibril formation is accelerated by mutations of proline residues to alanine in the acidic region. We performed replica exchange molecular dynamics simulations of the acidic and nonamyloid component (NAC) domains of the wild type and proline-to-alanine mutants of α-synuclein under various conditions. Our results showed that structural changes induced by a change in pH or an introduction of mutations lead to a reduction in mutual contacts between the NAC and acidic regions. Our data suggest that the highly charged acidic region of α-synuclein may act as an intramolecular chaperone by protecting the hydrophobic domain from aggregation. Understanding the function of such chaperone-like parts of fibril-forming proteins may provide novel insights into the mechanism of amyloid formation.

A Molecular Dynamics Study on Controlling the Self-Assembly of ß-Sheet Peptides with Designer Nanorings.

Recently, a rational approach for constructing ß-barrel protein mimics by the self-assembly of peptide-based building blocks has been demonstrated. We performed molecular dynamics simulations of nanoring formation by means of the self-assembly of designed ß-sheet-forming peptides. Several factors contributing to the stability of the nanoring structures with respect to size were investigated. Our simulations predicted that an optimal nanoring size may be achieved by minimizing repulsions due to steric hindrance between bulky groups while maintaining favorable hydrogen-bond interactions between neighboring ß-sheet chains. It was shown that mutations in a test peptide, in which all or half of the tryptophan residues were replaced by phenylalanine, could enable the assembly of stable nanoring structures with smaller pore sizes. Insights into the fundamental factors driving the formation of peptide-based nanostructures are expected to facilitate the design of novel functional bionanostructures.

Designer nanorings with functional cavities from self-assembling ß-sheet peptides.

ß-Barrel proteins that take the shape of a ring are common in many types of water-soluble enzymes and water-insoluble transmembrane pore-forming proteins. Since ß-barrel proteins perform diverse functions in the cell, it would be a great step towards developing artificial proteins if we can control the polarity of artificial ß-barrel proteins at will. Here, we describe a rational approach to construct ß-barrel protein mimics from the self-assembly of peptide-based building blocks. With this approach, the direction of the self-assembly process toward the formation of water-soluble ß-barrel nanorings or water-insoluble transmembrane ß-barrel pores could be controlled by the simple but versatile molecular manipulation of supramolecular building blocks. This study not only delineates the basic driving force that underlies the folding of ß-barrel proteins, but also lays the foundation for the facile fabrication of ß-barrel protein mimics, which can be developed as nanoreactors, ion- and small-molecule-selective pores, and novel antibiotics.