Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 81, Issue 7, Pages 1102-1112Publisher
WILEY-BLACKWELL
DOI: 10.1002/prot.24244
Keywords
protein folding; misfolding; negative design
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Funding
- Spanish Government [BFU2011-24595, BFU2012-40020, CSD2006-00023]
- Comunidad Autonoma de Madrid, AMAROUTO fellowship
- Deutsche Forschungsgemeinschaft [PO 1025/6]
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Proteins that need to be structured in their native state must be stable both against the unfolded ensemble and against incorrectly folded (misfolded) conformations with low free energy. Positive design targets the first type of stability by strengthening native interactions. The second type of stability is achieved by destabilizing interactions that occur frequently in the misfolded ensemble, a strategy called negative design. Here, we investigate negative design adopting a statistical mechanical model of the misfolded ensemble, which improves the usual Gaussian approximation by taking into account the third moment of the energy distribution and contact correlations. Applying this model, we detect and quantify selection for negative design in most natural proteins, and we analytically design protein sequences that are stable both against unfolding and against misfolding. Proteins 2013; 81:1102-1112. (c) 2013 Wiley Periodicals, Inc.
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