The last decade has seen astounding increases in our knowledge of how proteins fold, both <i>in vitro</i> and in living cells. Using experiments with ever-increasing levels of sophistication, combined with increases in the powers of simulation and computational methods, we can now monitor folding transitions on nsec-msec timescales in all-atom detail, watch proteins folding as they emerge from the ribosome, and witness the conformational fluctuations of individual protein molecules as they search for their native conformations on rugged energy landscapes. It is also now clear that proteins can misfold, sometimes frequently during folding, and, if this is left unchecked by molecular chaperones, this can result in disastrous consequences for the cell. Understanding the fundamental mechanism(s) of how misfolded proteins aggregate and how these species cause cellular dysfunction remains a significant challenge.<br/>In this lecture I will describe how different biophysical methods are being used to reveal the mechanism by which normally soluble proteins convert into amyloidogenic conformations, and how these findings are leading to new opportunities to prevent aggregation and possibly ameliorate disease. Specifically focussing on the peptides Abeta and amylin, I will show how small differences in conformation of these disordered peptides can give rise to remarkably different assembly kinetics, and how bimolecular collisions between protein variants can result in very different outcomes of assembly. The results reveal that the course of amyloid assembly can be exquisitely sensitive to the peptide sequence and/or the presence of chemical/post-translational modifications. This may explain, at least in part, the different timescales of disease progression in individuals with amyloid disease.<br/>

Conformational imprinting and amyloid disease

255th National Meeting (2018)

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