ArticleJournal of molecular biology2011
Structural origins of high apparent dielectric constants experienced by ionizable groups in the hydrophobic core of a protein.
Article in Journal of molecular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 41 citations in OpenAlex.
- A molten globule ensemble primes Arf1-GDP for the nucleotide switch.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Electronic Polarization Is Essential for the Stabilization and Dynamics of Buried Ion Pairs in Staphylococcal Nuclease Mutants.Journal of the American Chemical Society · 2022Article
- Biomolecular QM/MM Simulations: What Are Some of the "Burning Issues"?The journal of physical chemistry. B · 2021Article
- Conformational features and ionization states of Lys side chains in a protein studied using the stereo-array isotope labeling (SAIL) method.Magnetic resonance (Gottingen, Germany) · 2021Article
- A Second Backbone: The Contribution of a Buried Asparagine Ladder to the Global and Local Stability of a Leucine-Rich Repeat Protein.Biochemistry · 2019Article
- Article
- Reservoir pH replica exchange.The Journal of chemical physics · 2018Article
- Hydronium Ions Accompanying Buried Acidic Residues Lead to High Apparent Dielectric Constants in the Interior of Proteins.The journal of physical chemistry. B · 2018Article
- Structural and thermodynamic consequences of burial of an artificial ion pair in the hydrophobic interior of a protein.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Article
- Calculations of the electric fields in liquid solutions.The journal of physical chemistry. B · 2013Article
- Biomolecular electrostatics and solvation: a computational perspective.Quarterly reviews of biophysics · 2012Review
- Structural reorganization triggered by charging of Lys residues in the hydrophobic interior of a protein.Structure (London, England : 1993) · 2012Article
- Quantitative, directional measurement of electric field heterogeneity in the active site of ketosteroid isomerase.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- The high dielectric constant of staphylococcal nuclease is encoded in its structural architecture.Journal of the American Chemical Society · 2011Article
- Predicting extreme pKa shifts in staphylococcal nuclease mutants with constant pH molecular dynamics.Proteins · 2011Article
- Article
- Arginine residues at internal positions in a protein are always charged.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Thermodynamic principles for the engineering of pH-driven conformational switches and acid insensitive proteins.Biophysical chemistry · 2011Article
- Tunable pKa values and the basis of opposite charge selectivities in nicotinic-type receptors.Nature · 2011Article
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4 authors at 1 institution in 1 country.
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Abstract
The side chains of Lys66, Asp66, and Glu66 in staphylococcal nuclease are fully buried and surrounded mainly by hydrophobic matter, except for internal water molecules associated with carboxylic oxygen atoms. These ionizable side chains titrate with pK(a) values of 5.7, 8.8, and 8.9, respectively. To reproduce these pK(a) values with continuum electrostatics calculations, we treated the protein with high dielectric constants. We have examined the structural origins of these high apparent dielectric constants by using NMR spectroscopy to characterize the structural response to the ionization of these internal side chains. Substitution of Val66 with Lys66 and Asp66 led to increased conformational fluctuations of the microenvironments surrounding these groups, even under pH conditions where Lys66 and Asp66 are neutral. When Lys66, Asp66, and Glu66 are charged, the proteins remain almost fully folded, but resonances for a few backbone amides adjacent to the internal ionizable residues are broadened. This suggests that the ionization of the internal groups promotes a local increase in dynamics on the intermediate timescale, consistent with either partial unfolding or increased backbone fluctuations of helix 1 near residue 66, or, less likely, with increased fluctuations of the charged side chains at position 66. These experiments confirm that the high apparent dielectric constants reported by internal Lys66, Asp66, and Glu66 reflect localized changes in conformational fluctuations without incurring detectable global structural reorganization. To improve structure-based pK(a) calculations in proteins, we will need to learn how to treat this coupling between ionization of internal groups and local changes in conformational fluctuations explicitly.
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