ArticleProceedings of the National Academy of Sciences of the United States of America2019
How internal cavities destabilize a 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 30 papers.
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Who cites it
30 citing papers in PubMed.
- Disease-Associated Mutations Impact DNA Methyltransferase 1 Function through Dynamic Allosteric Effects and Solvent Exposure.Journal of chemical theory and computation · 2026Article
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- Function and Engineering of a Food Enzyme Under Coupled High-Temperature-Pressure Conditions: Insights from Molecular Dynamics Simulation and Experimental Validation.Foods (Basel, Switzerland) · 2025Article
- In Silico Strategies for Characterizing Inner Cavities of Lipid-Binding Proteins.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Dynamical features of smooth muscle actin pathological mutants: The arginine-257(258)-Cysteine cases.Computational and structural biotechnology journal · 2025Article
- SIGMA leverages protein structural information to predict the pathogenicity of missense variants.Cell reports methods · 2024Article
- Integration of food raw materials, food microbiology, and food additives: systematic research and comprehensive insights into sweet sorghum juice,Frontiers in microbiology · 2024Article
- Computational redesign of taxane-10β-hydroxylase for de novo biosynthesis of a key paclitaxel intermediate.Applied microbiology and biotechnology · 2023Article
- Changes in the hydrophobic network of the FliGiScience · 2023Article
- Redesign of γ-glutamyl transpeptidase from Bacillus subtilis for high-level production of L-theanine by cavity topology engineering.Applied microbiology and biotechnology · 2023Article
- Inside Out Computational Redesign of Cavities for Improving Thermostability and Catalytic Activity ofApplied and environmental microbiology · 2023Article
- High Pressure CPMG and CEST Reveal That Cavity Position Dictates Distinct Dynamic Disorder in the PP32 Repeat Protein.The journal of physical chemistry. B · 2022Article
- Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core.Scientific reports · 2022Article
- Unraveling multi-state molecular dynamics in single-molecule FRET experiments. II. Quantitative analysis of multi-state kinetic networks.The Journal of chemical physics · 2022Article
- Allosteric Communication in the Multifunctional and Redox NQO1 Protein Studied by Cavity-Making Mutations.Antioxidants (Basel, Switzerland) · 2022Article
- Thermoadaptation in an Ancestral Diterpene Cyclase by Altered Loop Stability.The journal of physical chemistry. B · 2022Article
- Biomolecules under Pressure: Phase Diagrams, Volume Changes, and High Pressure Spectroscopic Techniques.International journal of molecular sciences · 2022Review
- Combining High-Pressure NMR and Geometrical Sampling to Obtain a Full Topological Description of Protein Folding Landscapes: Application to the Folding of Two MAX Effectors fromInternational journal of molecular sciences · 2022Article
- The contribution of electrostatics to hydrogen exchange in the unfolded protein state.Biophysical journal · 2021Article
- Activation of Cytochrome C Peroxidase Function Through Coordinated Foldon Loop Dynamics upon Interaction with Anionic Lipids.Journal of molecular biology · 2021Article
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9 authors.
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Abstract
Although many proteins possess a distinct folded structure lying at a minimum in a funneled free energy landscape, thermal energy causes any protein to continuously access lowly populated excited states. The existence of excited states is an integral part of biological function. Although transitions into the excited states may lead to protein misfolding and aggregation, little structural information is currently available for them. Here, we show how NMR spectroscopy, coupled with pressure perturbation, brings these elusive species to light. As pressure acts to favor states with lower partial molar volume, NMR follows the ensuing change in the equilibrium spectroscopically, with residue-specific resolution. For T4 lysozyme L99A, relaxation dispersion NMR was used to follow the increase in population of a previously identified "invisible" folded state with pressure, as this is driven by the reduction in cavity volume by the flipping-in of a surface aromatic group. Furthermore, multiple partly disordered excited states were detected at equilibrium using pressure-dependent H/D exchange NMR spectroscopy. Here, unfolding reduced partial molar volume by the removal of empty internal cavities and packing imperfections through subglobal and global unfolding. A close correspondence was found for the distinct pressure sensitivities of various parts of the protein and the amount of internal cavity volume that was lost in each unfolding event. The free energies and populations of excited states allowed us to determine the energetic penalty of empty internal protein cavities to be 36 cal⋅Å
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