ArticleThe journal of physical chemistry. B2013
Engineering folding dynamics from two-state to downhill: application to λ-repressor.
Article in The journal of physical chemistry. B, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- pH-Dependent cooperativity and existence of a dry molten globule in the folding of a miniprotein BBL.Physical chemistry chemical physics : PCCP · 2018Article
- Reconciling Intermediates in Mechanical Unfolding Experiments with Two-State Protein Folding in Bulk.The journal of physical chemistry letters · 2016Article
- Markov state models of protein misfolding.The Journal of chemical physics · 2016Article
- Dependence of internal friction on folding mechanism.Journal of the American Chemical Society · 2015Article
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4 authors.
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Abstract
One strategy for reaching the downhill folding regime, primarily exploited for the λ(6-85) protein fragment, consists of cumulatively introducing mutations that speed up folding. This is an experimentally demanding process where chemical intuition usually serves as a guide for the choice of amino acid residues to mutate. Such an approach can be aided by computational methods that screen for protein engineering hot spots. Here we present one such method that involves sampling the energy landscape of the pseudo-wild-type protein and investigating the effect of point mutations on this landscape. Using a novel metric for the cooperativity, we identify those residues leading to the least cooperative folding. The folding dynamics of the selected mutants are then directly characterized and the differences in the kinetics are analyzed within a Markov-state model framework. Although the method is general, here we present results for a coarse-grained topology-based simulation model of λ-repressor, whose barrier is reduced from an initial value of ∼4 k(B)T at the midpoint to ∼1 k(B)T, thereby reaching the downhill folding regime.
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