Frustration in the energy landscapes of multidomain protein misfolding

Abstract

Frustration from strong interdomain interactions can make misfolding a more severe problem in multidomain proteins than in singledomain proteins. On the basis of bioinformatic surveys, it has been suggestedthat loweringthesequence identitybetween 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 β-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. Domainswapped contacts compete with self-recognition contacts informing 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.