Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins

Abstract

We have developed a statistical mechanics algorithm, TANGO, to predict protein aggregation. TANGO is based on the physico-chemical principles of beta-sheet formation, extended by the assumption that the core regions of an aggregate are fully buried. Our algorithm accurately predicts the aggregation of a data set of 179 peptides compiled from the literature as well as of a new set of 71 peptides derived from human disease-related proteins, including prion protein, lysozyme and beta2-microglobulin. TANGO also correctly predicts pathogenic as well as protective mutations of the Alzheimer beta-peptide, human lysozyme and transthyretin, and discriminates between beta-sheet propensity and aggregation. Our results confirm the model of intermolecular beta-sheet formation as a widespread underlying mechanism of protein aggregation. Furthermore, the algorithm opens the door to a fully automated, sequence-based design strategy to improve the aggregation properties of proteins of scientific or industrial interest.

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

“…We cannot, of course, exclude the possibility that our ancestral sequences contain biases or errors that are undetectable from sequence analysis but still impactful. Similarly, we analysed our LeuB sequences for their aggregation potential (using TANGO;Fernandez-Escamilla et al 2004) and, again, found no trend with inferred evolutionary age. All of our LeuBs are predicted to have a low average percentage aggregation per residue (\2 %) and, in fact, BCVX contains the greatest number of aggregation-prone residues and aggregation-prone stretches.…”

Quantitative approaches to defining normal and aberrant protein homeostasis

“…Considerable attention has been devoted to exploring the nature and origin of such disorders from a structural viewpoint and to understanding the manner in which the balance between normal and aberrant conformational transitions can be perturbed. 20 Several studies have involved in vitro studies coupled with computer simulations, [20][21][22][23] and many others have been concerned with the goal of relating processes studied in atomic detail in the test tube to their quantitative effects in living systems. [24][25][26] Moreover, recent findings suggest that further developments in this area could have much more general relevance to understanding the way in which well-established physical and chemical principles can provide new insights into the apparent complexity of biology.…”

Protein folding: Then and now

“…Traditional all-atom molecular dynamics simulations have been carried out to model the aggregation of disease-related peptides such as Aβ and polyglutamine [235][236][237]. Other techniques seek to identify which parts within larger proteins are responsible for their aggregation behavior, resulting in the identification of sequence stretches in various proteins that are "amyloidogenic," or "hot spots" for aggregation [238][239][240]. Underlying this work is the idea that evolution acts to prevent aggregation by burying aggregation-prone protein sequences or otherwise prohibiting their apposition in protein structures and during folding 1 .…”