Abstract
Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease.
Highlights
Less than two thousands protein folds have been identified in nature [1, 2], indicating that similar folds can be adopted by large numbers of sequences
The structural properties of these intrinsically disordered proteins are difficult to study using classical techniques because of their rapid fluctuations that result in high conformational polymorphism
We find that relatively large mechanical stability may arise from structures with large secondary structure content (SS, measured as the percentages of residues belonging to αhelices, β-strands and hydrogen-bonded turns) and from those with SS of about 30%
Summary
Less than two thousands protein folds have been identified in nature [1, 2], indicating that similar folds can be adopted by large numbers of sequences. These folds have been characterized and classified in the CATH database [3]. The score is obtained through an algorithm for protein comparison based on secondary structure alignment [5]. They explored, in their own words [4], the universe of protein structures beyond the Protein Data Bank. They argued that there must be an evolutionary principle that favors shorter loops and directs the evolution to a certain spot in the universe of possible conformations
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