RESUMEN
DNA strands have to sample numerous states to find the alignment that maximizes Watson-Crick-Franklin base pairing. This process depends strongly on sequence, which affects the stability of the native duplex as well as the prevalence of non-native inter- and intramolecular helices. We present a theory that describes DNA hybridization as a three-stage process: diffusion, registry search, and zipping. We find that non-specific binding affects each of these stages in different ways. Mis-registered intermolecular binding in the registry search stage helps DNA strands sample different alignments and accelerates the hybridization rate. Non-native intramolecular structure affects all three stages by rendering portions of the molecule inert to intermolecular association, limiting mis-registered alignments to be sampled, and impeding the zipping process. Once in-register base pairs are formed, the stability of the native structure is important to hold the molecules together long enough for non-native contacts to break.
Asunto(s)
ADN , Conformación de Ácido Nucleico , Termodinámica , Hibridación de Ácido Nucleico , Emparejamiento Base , ADN/genética , ADN/químicaRESUMEN
Amyloid aggregates are found in many neurodegenerative diseases, including Huntington's, Alzheimer's, and prion diseases. The precise role of the aggregates in disease progression has been difficult to elucidate because of the diversity of aggregated states they can adopt. Here, we study the formation of fibrils and oligomers by exon 1 of huntingtin protein. We show that the oligomer states are consistent with polymer micelles that are limited in size by the stretching entropy of the polyglutamine region. The model shows how the sequences flanking the amyloid core modulate aggregation behavior. The N17 region promotes aggregation through weakly attractive interactions, whereas the C38 tail opposes aggregation via steric repulsion. We also show that the energetics of cross-ß stacking by polyglutamine would produce fibrils with many alignment defects, but minor perturbations from the flanking sequences are sufficient to reduce the defects to the level observed in experiment. We conclude with a discussion of the implications of this model for other amyloid-forming molecules.