Towards the design of anti-amyloid short peptide helices.

Irena Roterman, ,Leszek Konieczny,Mateusz Banach

doi:10.6026/97320630014001

Abstract

A set of short peptide sequences susceptible to fibrillar aggregation produces sequneces capable of arresting elongation of amyloid fibrils. The "stop" signals are short helices customized for each individual target. Such a helix should exhibit high amphiphilicity, with differing conditions present on each side (one side should be highly hydrophilic to enable water to interact with the aggregate, while the other side must retain a local distribution of hydrophobicity which matches that of the terminal portion of the fibril). The emergence and elongation of fibrillary forms resulting from linear propagation of local hydrophobicity peaks is shown using the fuzzy oil drop model.

Highlights

An important voice in the discussion regarding Alzheimer’s disease comes from the psychologist community, which attempts to identify objective causes for the disase [1]
According to the fuzzy oil drop model [14] (FOD) the water environment plays a decisive role in this process – as noted by other authors who recognize the importance of hydrophobic interactions for amyloid formation
The pattern for the design of a “stop” signal is provided by a lyase – bacterial chondroitinase b pectate lyase (PDB ID: 1DBG) [32]. This protein contains a solenoid fragment with a notably linear arrangement of hydrophobic and hydrophilic “bands”. This type of structure might propagate indefinitely in the absence of an amphiphilic helical stopper, whose hydrophilic side faces the water environment while the hydrophobic side remains in contact with the fibril

Summary

Introduction

An important voice in the discussion regarding Alzheimer’s disease comes from the psychologist community, which attempts to identify objective causes for the disase [1]. The most promising avenue of research appears to involve short synthetic peptides containing the self-recognition motif of the protein and engineered to destabilize the abnormal conformation, which might be useful to correct protein misfolding [6]. Such peptides are sometimes referred to as minichaperones. The search for novel drugs is not, based on amyloid plaque formation mechanisms. According to the fuzzy oil drop model [14] (FOD) the water environment plays a decisive role in this process – as noted by other authors who recognize the importance of hydrophobic interactions for amyloid formation. The external environment is recognized as a factor in amyloidogenesis [17]

Methods

Results

Conclusion