ArticleThe journal of physical chemistry. B2014
Filling up the heme pocket stabilizes apomyoglobin and speeds up its folding.
Article in The journal of physical chemistry. B, 2014. 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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Who cites it
4 citing papers in PubMed, 8 citations in OpenAlex.
- Non-Native Structures of Apomyoglobin and Apoleghemoglobin in Folding Intermediates Related to the Protein Misfolding.Molecules (Basel, Switzerland) · 2023Review
- Insights from molecular dynamics simulations for computational protein design.Molecular systems design & engineering · 2017Article
- Folding of apomyoglobin: Analysis of transient intermediate structure during refolding using quick hydrogen deuterium exchange and NMR.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2017Review
- Fast-folding proteins under stress.Cellular and molecular life sciences : CMLS · 2015Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Wild type apomyoglobin folds in at least two steps: the ABGH core rapidly, followed much later by the heme-binding CDEF core. We hypothesize that the evolved heme-binding function of the CDEF core frustrates its folding: it has a smaller contact order and is no more complex topologically than ABGH, and thus, it should be able to fold faster. Therefore, filling up the empty heme cavity of apomyoglobin with larger, hydrophobic side chains should significantly stabilize the protein and increase its folding rate. Molecular dynamics simulations allowed us to design four different mutants with bulkier side chains that increase the native bias of the CDEF region. In vitro thermal denaturation shows that the mutations increase folding stability and bring the protein closer to two-state behavior, as judged by the difference of fluorescence- and circular dichroism-detected protein stability. Millisecond stopped flow measurements of the mutants exhibit refolding kinetics that are over 4 times faster than the wild type's. We propose that myoglobin-like proteins not evolved to bind heme are equally stable, and find an example. Our results illustrate how evolution for function can force proteins to adapt frustrated folding mechanisms, despite having simple topologies.
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Registered trials
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