Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0061222
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Funding
- Government of India-DAE
- Govt of India-DST-Ramanujan Fellowship [SR/S2/RJN-63/2009]
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When an amino-acid sequence cannot be optimized for both folding and function, folding can get compromised in favor of function. To understand this tradeoff better, we devise a novel method for extracting the function-less folding-motif of a protein fold from a set of structurally similar but functionally diverse proteins. We then obtain the beta-trefoil folding-motif, and study its folding using structure-based models and molecular dynamics simulations. Comparison with the folding of wild-type beta-trefoil proteins shows that function affects folding in two ways: In the slower folding interleukin-1 beta, binding sites make the fold more complex, increase contact order and slow folding. In the faster folding hisactophilin, residues which could have been part of the folding-motif are used for function. This reduces the density of native contacts in functional regions and increases folding rate. The folding-motif helps identify subtle structural deviations which perturb folding. These may then be used for functional annotation. Further, the folding-motif could potentially be used as a first step in the sequence design of function-less scaffold proteins. Desired function can then be engineered into these scaffolds.
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