期刊
BIOPHYSICAL JOURNAL
卷 93, 期 6, 页码 1923-1937出版社
CELL PRESS
DOI: 10.1529/biophysj.107.110080
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Intrinsically disordered proteins (IDPs) are unfolded under physiological conditions. Here we ask if archetypal IDPs in aqueous milieus are best described as swollen disordered coils in a good solvent or collapsed disordered globules in a poor solvent. To answer this question, we analyzed data from molecular simulations for a 20-residue polyglutamine peptide and concluded, in accord with experimental results, that water is a poor solvent for this system. The relevance of monomeric polyglutamine is twofold: It is an archetypal IDP sequence and its aggregation is associated with nine neurodegenerative diseases. The main advance in this work lies in our ability to make accurate assessments of solvent quality from analysis of simulations for a single, rather than multiple chain lengths. We achieved this through the proper design of simulations and analysis of order parameters that are used to describe conformational equilibria in polymer physics theories. Despite the preference for collapsed structures, we find that polyglutamine is disordered because a heterogeneous ensemble of conformations of equivalent compactness is populated at equilibrium. It is surprising that water is a poor solvent for polar polyglutamine and the question is: why? Our preliminary analysis suggests that intrabackbone interactions provide at least part of the driving force for the collapse of polyglutamine in water. We also show that dynamics for conversion between distinct conformations resemble structural relaxation in disordered, glassy systems, i.e., the energy landscape for monomeric polyglutamine is rugged. We end by discussing generalizations of our methods to quantitative studies of conformational equilibria of other low-complexity IDP sequences.
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