PACT - Prediction of Amyloid Cross-interaction by Threading

Abstract

Amyloids are protein aggregates most commonly known for their role in the development of severe neurodegenerative diseases, such as Alzheimer's or Parkinson's disease. However, the unique features of such structures were also beneficially utilized by many organisms for a wide range of physiological roles e.g., biofilm formation and hormone storage. More recent studies have shown that in some cases presence of amyloid aggregates can affect aggregatio kinetics of other proteins. These so-called cross interactions may be crucial for understanding comorbidity of amyloid related diseases, including Alzheimer's disease and type II diabetes. Despite the importance of the process, our understanding of the phenomena is still very limited due to costly and time consuming experiments required to study theinteractions. To overcome this problem, we developed the PACT method. The method is based on modeling of heterogenous fibrils, formed by two amyloidogenic peptides. The resulting structural model is then assessed based on DOPE statistical potential implemented in the Modeller method, based on template based modeling. The main assumption of the method is that pairs of interacting amyloids will be energetically more favorable than negative cases. Importantly, the method can work with long protein fragments and, as a purely physicochemical model, it relies very little on training data. The method, for the first time, opens the possibility of high throughput study of amyloid interactions. The tool is available at: https://github.com/KubaWojciechowski/PACT

Amyloid, a Jekyll and Hyde Molecule Inducing Neuronal Decline and Cognitive Dysfunction is Also a Unique Molecular Template used in Nano-electronics, Light Capture Photovoltaics, and Biosensors in Neuromorphic Computing.

“…Development of methods to produce controlled amyloid fibrils in vitro is an important innovation and opens the door for the design of new biomaterials exploiting the superior structural properties of amyloid fibrils and the inherent diversity of peptide sequences [107]. A number of bioinformatics [108,109] and computational studies [110][111][112][113][114][115][116][117][118][119] have examined the peptide sequences of amyloid proteins [120][121][122][123][124][125][126] to better understand the aggregation process and to determine peptide sequences that initiate and propagate assembly of fibrillar material. Software developed for the prediction of peptide sequences with inherent amyloid fibril forming capability should be very useful in the design of specific amyloid nano-components for specific tissue engineering applications [127][128][129] and in therapeutics development of compounds that prevent amyloid assembly.…”