2, University of Cambridge, Cambridge, , United Kingdom
3, Stanford University, Stanford, California, United States
4, Aarhus University, Aarhus, , Denmark
5, University of Nottingham, Nottingham, , United Kingdom
Self–assembly is a process by which molecules of fundamental importance for life, such as proteins and DNA, are formed. Apart from these examples of beneficial self–assembly, aberrant assembly of pathogenic proteins, such as amyloids, may occur. The latter is responsible for several highly–debilitating neurodegenerative disorders which remains currently incurable, such as Alzheimer’s and Parkinson’s diseases. On the other hand, biomaterials inspired by amyloids, such as the ones using diphenylalanine as the building block, are successfully employed in a large selection of functional materials. Delving into amyloid self–assembly is therefore highly relevant for both medical and engineering fields.
In this work, we show how acetylation of KLVFF, a fragment of the pathogenic β-amyloid protein considered to be an aggregation inhibitor, can turn this peptide into a fast self-assembling molecule, able to reach macroscopic size in seconds, even when mild incubation conditions are applied. The driving force for such assembly is a combination of local charge modification and diphenylalanine propensity to assemble into stable structures. We also describe the metastability of KLVFF and show that it can directed by chemical modifications as opposed to peptide length. To prove our hypothesis, we followed and compared the self–assembly of unmodified KLVFF with its amidated and acetylated counterparts. Amidated KLVFF can form amyloid fibrils; we observed folding events occurring in as little as 60 msec.
We exploited synchrotron radiation circular dichroism and a vaste array of microscopies including atomic force and electron microscopy, and scanning electron microscopy. We believe that the remarkable ability of single KLVFF molecules to assemble as highly ordered macroscopic structures in seconds will make it highly desirable for applications of acetylated KLVFF as a rapid–forming templating material.