ArticleProceedings of the National Academy of Sciences of the United States of America2019
Networks of electrostatic and hydrophobic interactions modulate the complex folding free energy surface of a designed βα protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 37 citations in OpenAlex.
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- Functional customization of peptide linkers in fusion proteins through multimodal deep learning approach.Synthetic and systems biotechnology · 2026Article
- Surface electrostatic networks control hydrophobic core remodeling in a pH-dependent switching protein.bioRxiv : the preprint server for biology · 2026Article
- Rational Engineering of Cellobiose 2-Epimerase Through Flexible Loop Modulation and Structure-Guided Sequence Alignment for Enhanced Lactulose Synthesis.Biomolecules · 2026Article
- Molecular choreography of sludge extracellular polymeric substances-From biomolecule identification to energetics and assembly dynamics.PNAS nexus · 2025Article
- Aromatic-aromatic interactions drive fold switch of GA95 and GB95 with three residue difference.Chemical science · 2025Article
- Temporal and spatial resolution of distal protein motions that activate hydrogen tunneling in soybean lipoxygenase.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- A Method for Assessing the Robustness of Protein Structures by Randomizing Packing Interactions.Frontiers in molecular biosciences · 2022Article
- Evolution of the folding landscape of effector caspases.The Journal of biological chemistry · 2021Article
- The Stability Landscape of de novo TIM Barrels Explored by a Modular Design Approach.Journal of molecular biology · 2021Article
- ProteinTools: a toolkit to analyze protein structures.Nucleic acids research · 2021Article
- Voronoia 4-ever.Nucleic acids research · 2021Article
- Evolution, folding, and design of TIM barrels and related proteins.Current opinion in structural biology · 2021Review
- Protein sequence design by conformational landscape optimization.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Slow Transition Path Times Reveal a Complex Folding Barrier in a Designed Protein.Frontiers in chemistry · 2020Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
The successful de novo design of proteins can provide insights into the physical chemical basis of stability, the role of evolution in constraining amino acid sequences, and the production of customizable platforms for engineering applications. Previous guanidine hydrochloride (GdnHCl; an ionic denaturant) experiments of a designed, naturally occurring βα fold, Di-III_14, revealed a cooperative, two-state unfolding transition and a modest stability. Continuous-flow mixing experiments in our laboratory revealed a simple two-state reaction in the microsecond to millisecond time range and consistent with the thermodynamic results. In striking contrast, the protein remains folded up to 9.25 M in urea, a neutral denaturant, and hydrogen exchange (HDX) NMR analysis in water revealed the presence of numerous high-energy states that interconvert on a time scale greater than seconds. The complex protection pattern for HDX corresponds closely with a pair of electrostatic networks on the surface and an extensive network of hydrophobic side chains in the interior of the protein. Mutational analysis showed that electrostatic and hydrophobic networks contribute to the resistance to urea denaturation for the WT protein; remarkably, single charge reversals on the protein surface restore the expected urea sensitivity. The roughness of the energy surface reflects the densely packed hydrophobic core; the removal of only two methyl groups eliminates the high-energy states and creates a smooth surface. The design of a very stable βα fold containing electrostatic and hydrophobic networks has created a complex energy surface rarely observed in natural proteins.
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