Folding and Aggregation of Designed Proteins

TL;DR

This study uses lattice-model simulations to explore how designed proteins fold and aggregate, revealing that both ordered and disordered aggregation originate from elementary structures involved in folding, with implications for understanding disease-related protein deposits.

Contribution

The paper demonstrates that both types of protein aggregation stem from elementary structures that form the folding nucleus, providing new insights into the aggregation process and its evolutionary aspects.

Findings

Ordered and disordered aggregation originate from elementary structures.

Elementary structures are involved in the formation of the folding nucleus.

Residues involved in elementary structures are evolutionarily conserved.

Abstract

Studies of how protein fold have shown that the way protein clumps form in the test tube is similar to how proteins form the so-called ``amyloid'' deposits that are the pathological signal of a variety of diseases, among them the memory disorder Alzheimer's. Protein aggregation have traditionally been connected to either unfolded or native states. Inclusion body formation (disordered aggregation) has been assumed to arise from hydrophobic aggregation of the unfolded or denaturated states, while the amyloid fibrils (ordered aggregation) have been assumed to arise from native-like conformations in a process analogous to the polymerization of hemoglobin S. Making use of lattice-model simulations we find that both ordered and disordered aggregation arise from elementary structures which eventually build the folding nucleus of the heteropolymers, and takes place when some of the most strongly interacting amino acids establish their contacts leading to the formation of a specific subset of the native structure. These elementary structures can be viewed as the partially folded intermediates suggested to be involved in the aggregation of a number of proteins. These results have evolutionary implications, as the elementary structures forming the folding core of designed proteins contain the residues which are conserved among the members of homologous sequences.