Lipids in Protein Misfolding

Nikita V. Dovidchenko, Oxana V. Galzitskaya, Dovidchenko, Nikita V., Galzitskaya, Oxana V.

This chapter describes computational approaches to study amyloid formation. The first part addresses identification of potential amyloidogenic regions in the amino acid sequences of proteins and peptides. Next, we discuss nucleation and aggregation sites in protein folding and misfolding. The last part describes up-to-date kinetic models of amyloid fibrils formation. Numerous studies show that protein misfolding is initiated by specific amino acid segments with high amyloid-forming propensity. The ability to identify and, ultimately, block such segments is very important. To this end, many prediction algorithms have been developed which vary greatly in their effectiveness. We compared the predictions for 30 proteins by using different methods and found that, at best, only 50 % of residues in amyloidogenic segments were predicted correctly. The best results were obtained by using the meta-servers that combine several independent approaches, and by the method PASTA2. Thus, correct prediction of amyloidogenic segments remains a difficult task. Additional data and new algorithms that are becoming available are expected to improve the accuracy of the prediction methods, particularly if they use 3D structural information on the target proteins. At the same time, our understanding of the kinetics of fibril formation is more advanced. The current kinetic models outlined in this chapter adequately describe the key features of amyloid nucleation and growth. However, the underlying structural details are less clear, not least because of the apparently different mechanisms of amyloid fibril formation which are discussed. Ultimately, the detailed understanding of the structural basis for amyloidogenesis should help develop rational therapies to block this pathogenic process.