Study of the potential role of tilted peptides in transconformation: Theoritical analysis of amyloidogenic proteins

Amyloidogenic proteins are of interest in the study of transconformational processes because they undergo a major conformational change leading to amyloid fibrils formation by a self-assembly of their misfolded form. 
Amyloid fibrils are implied in several diseases such as Alzheimer, Parkinson or Creutzfeldt-Jakob diseases. At a structural point of view they have varying lengths up to few micrometers, they are unbranched and the individual β strands are oriented perpendicular to the long axis of the fibril. Moreover, the conformational changes induce an increase in the β content. However little is known about the mechanisms of transconformation, the subsequent aggregation and the toxicity of these proteins. Study of these misfolded proteins, and particularly the study of their conformation, is difficult due to their high tendency to aggregate in solution. 
Regarding the transconformational mechanisms, it’s interesting to study the potential role of tilted peptides because they possess several properties that could be involved in this process. They can adopt  or β conformation depending on the environment and when helical they can destabilize the hydrophilic/hydrophobic interface of an organised system. They were notably found in the domain undergoing transconformation in the A protein (Alzheimer’s disease) and in PrP (prion diseases). They could have an important role in the first step of the transconformational process ; their destabilizing properties could also be implied in the toxicity of these proteins. 
The aim of this study is to analyse the sequence of amyloidogenic proteins undergoing  to  transition, looking for tilted peptides. From their primary sequence, Eisenberg’s hydrophobic moment plot, hydrophobic cluster analysis, Jähnig’s plot and several methods for the prediction of secondary structure have been carried out. Fragments corresponding to potential tilted peptides following different criteria (mean of hydrophobicity, length, …) were 3D built and their insertion into a simplified bilayer was simulated using the IMPALA method. A detailed study of the literature should provide more information about the particular properties of these sequences and the existence of these tilted peptides must be demonstrated by experimental techniques. The tilted fragment from -synuclein (Parkinson’s disease) is under current investigations.