Comparative studies of disordered proteins with similar sequences: application to A?40 and A?42.

ABSTRACT: Quantitative comparisons of intrinsically disordered proteins (IDPs) with similar sequences, such as mutant forms of the same protein, may provide insights into IDP aggregation-a process that plays a role in several neurodegenerative disorders. Here we describe an approach for modeling IDPs with similar sequences that simplifies the comparison of the ensembles by utilizing a single library of structures. The relative population weights of the structures are estimated using a Bayesian formalism, which provides measures of uncertainty in the resulting ensembles. We applied this approach to the comparison of ensembles for A?40 and A?42. Bayesian hypothesis testing finds that although both A? species sample ?-rich conformations in solution that may represent prefibrillar intermediates, the probability that A?42 samples these prefibrillar states is roughly an order of magnitude larger than the frequency in which A?40 samples such structures. Moreover, the structure of the soluble prefibrillar state in our ensembles is similar to the experimentally determined structure of A? that has been implicated as an intermediate in the aggregation pathway. Overall, our approach for comparative studies of IDPs with similar sequences provides a platform for future studies on the effect of mutations on the structure and function of disordered proteins.

SUBMITTER: Fisher CK 

PROVIDER: S-EPMC3617440 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature