Size and topology modulate the effects of frustration in protein folding

Abstract

The presence of conflicting interactions, or frustration, determines how fast biomolecules can explore their configurational landscapes. Recent experiments have provided cases of systems with slow reconfiguration dynamics, perhaps arising from frustration. While it is well known that protein folding speed and mechanism are strongly affected by the protein native structure, it is still unknown how the response to frustration is modulated by the protein topology. We explore the effects of nonnative interactions in the reconfigurational and folding dynamics of proteins with different sizes and topologies. We find that structural correlations related to the folded state size and topology play an important role in determining the folding kinetics of proteins that otherwise have the same amount of nonnative interactions. In particular, we find that the reconfiguration dynamics of α-helical proteins are more susceptible to frustration than β-sheet proteins of the same size. Our results may explain recent experimental findings and suggest that attempts to measure the degree of frustration due to nonnative interactions might be more successful with α-helical proteins.

Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy

“…Furthermore, the contact between nonnative interactions can destructively interfere with protein configurational landscapes. 22 Our data suggest that a single residue change within the core of the minimally frustrated N-TnC hub directly loosens its structural rigidity, which impacts the conformational dynamics of other motifs within cTnC. This leads to altered Ca 2+ sensitivity of isometric force and altered contractile kinetics, which trigger cardiomyopathy in a mouse model.…”

Defects and defect engineering in Soft Matter

“…As a result, the speed and the mechanism of protein folding are strongly affected by the protein native structure and the density of frustrations. 450 Clementi and coworkers proposed a model that demonstrates that there is a range of frustration (defect density) that lowers the barrier to fold proteins. In addition, the impact of frustration defects induced by nonnative heterogeneity on protein folding systematically depends on the native state size and topology.…”

“…The suggested interplay between nonnative interactions and protein topology can explain the misfolding behavior of a and b proteins of similar size. 450 Another type of defect in the self-assembly process of biological systems is the oppositely charged disclination. These defects have been reported in the hierarchical self-assembly of microtubular bundles.…”

The C-terminal domain of transcription factor RfaH: Folding, fold switching and energy landscape

“…and does not extend to all fold classes [17][18][19]. The sequences of metamorphic proteins have diverged from their homologs to the point of nearly adopting a new unique fold.…”