Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 5, Pages 1680-1685Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222130110
Keywords
aggregation; funnel
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Funding
- National Institute of General Medical Sciences [R01 GM44557, P01 GM071862]
- D. R. Bullard-Welch Chair at Rice University
- Direct For Mathematical & Physical Scien
- Division Of Physics [1308264] Funding Source: National Science Foundation
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Frustration from strong interdomain interactions can make misfolding a more severe problem in multidomain proteins than in single-domain proteins. On the basis of bioinformatic surveys, it has been suggested that lowering the sequence identity between neighboring domains is one of nature's solutions to the multidomain misfolding problem. We investigate folding of multidomain proteins using the associative-memory, water-mediated, structure and energy model (AWSEM), a predictive coarse-grained protein force field. We find that reducing sequence identity not only decreases the formation of domain-swapped contacts but also decreases the formation of strong self-recognition contacts between beta-strands with high hydrophobic content. The ensembles of misfolded structures that result from forming these amyloid-like interactions are energetically disfavored compared with the native state, but entropically favored. Therefore, these ensembles are more stable than the native ensemble under denaturing conditions, such as high temperature. Domain-swapped contacts compete with self-recognition contacts in forming various trapped states, and point mutations can shift the balance between the two types of interaction. We predict that multidomain proteins that lack these specific strong interdomain interactions should fold reliably.
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