Navigating Homogeneous Paths through Amyloidogenic and Non-Amyloidogenic Hexapeptides

TL;DR

This paper demonstrates that a computational amyloid predictor can connect any two predicted amyloidogenic or non-amyloidogenic hexapeptides through a short path of similar peptides, revealing a structured landscape of peptide properties.

Contribution

It shows that the Budapest Amyloid Predictor, and similar linear SVM-based models, can connect predicted peptides via short paths in a graph based on single-residue differences.

Findings

Predicted amyloidogenic peptides are connected by paths of length at most 6.

The property holds for both amyloidogenic and non-amyloidogenic predictions.

The result is applicable to any linear SVM-based predictor.

Abstract

Hexapeptides are increasingly applied as model systems for studying the amyloidogenecity properties of oligo- and polypeptides. It is possible to construct 64 million different hexapeptides from the twenty proteinogenic amino acid residues. Today's experimental amyloid databases contain only a fraction of these annotated hexapeptides. For labeling all the possible hexapeptides as "amyloidogenic" or "non-amyloidogenic" there exist several computational predictors with good accuracies. It may be of interest to define and study a simple graph structure on the 64 million hexapeptides as nodes when two hexapeptides are connected by an edge if they differ by only a single residue. For example, in this graph, HIKKLM is connected to AIKKLM, or HIKKNM, or HIKKLC, but it is not connected with an edge to VVKKLM or HIKNPM. In the present contribution, we consider our previously published artificial intelligence-based tool, the Budapest Amyloid Predictor (BAP for short), and demonstrate a spectacular property of this predictor in the graph defined above. We show that for any two hexapeptides predicted to be "amyloidogenic" by the BAP predictor, there exists an easily constructible path of length at most 6 that passes through neighboring hexapeptides all predicted to be "amyloidogenic" by BAP. For example, the predicted amyloidogenic ILVWIW and FWLCYL hexapeptides can be connected through the length-6 path ILVWIW-IWVWIW-IWVCIW-IWVCIL-FWVCIL-FWLCIL-FWLCYL in such a way that the neighbors differ in exactly one residue, and all hexapeptides on the path are predicted to be amyloidogenic by BAP. The symmetric statement also holds for non-amyloidogenic hexapeptides. It is noted that the mentioned property of the Budapest Amyloid Predictor \url{https://pitgroup.org/bap} is not proprietary; it is also true for any linear Support Vector Machine (SVM)-based predictors.