ArticleBiochemistry2010
Conformational consequences of ionization of Lys, Asp, and Glu buried at position 66 in staphylococcal nuclease.
Article in Biochemistry, 2010. 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, 62 citations in OpenAlex.
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- Accurate and Transferable Reactive Molecular Dynamics Models from Constrained Density Functional Theory.The journal of physical chemistry. B · 2021Article
- Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework.Journal of chemical theory and computation · 2021Article
- An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity.The Biochemical journal · 2020Article
- Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2020Article
- Hydronium Ions Accompanying Buried Acidic Residues Lead to High Apparent Dielectric Constants in the Interior of Proteins.The journal of physical chemistry. B · 2018Article
- Origin of pKThe journal of physical chemistry. B · 2017Article
- Structural and Biochemical Studies on the Reaction Mechanism of Uridine-Cytidine Kinase.The protein journal · 2015Article
- Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.PLoS computational biology · 2015Article
- Protein-protein docking with dynamic residue protonation states.PLoS computational biology · 2014Article
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- Uncovering the determinants of a highly perturbed tyrosine pKa in the active site of ketosteroid isomerase.Biochemistry · 2013Article
- Assessing the chemical accuracy of protein structures via peptide acidity.Biophysical chemistry · 2013Article
- Biomolecular electrostatics and solvation: a computational perspective.Quarterly reviews of biophysics · 2012Review
- Accommodation of a central arginine in a transmembrane peptide by changing the placement of anchor residues.The journal of physical chemistry. B · 2012Article
- Rapid calculation of protein pKa values using Rosetta.Biophysical journal · 2012Article
- Structural reorganization triggered by charging of Lys residues in the hydrophobic interior of a protein.Structure (London, England : 1993) · 2012Article
- The high dielectric constant of staphylococcal nuclease is encoded in its structural architecture.Journal of the American Chemical Society · 2011Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The pK(a) values measured previously for the internal Lys-66, Asp-66, and Glu-66 in variants of a highly stable form of staphylococcal nuclease are shifted by as many as 5 pK(a) units relative to normal pK(a) values in water. These shifts cannot be reproduced with continuum electrostatics calculations with static structures unless the protein is treated with high dielectric constants near 10. These high apparent dielectric constants are inconsistent with the highly hydrophobic microenvironments of the ionizable moieties in crystal structures. To examine the origins of these high apparent dielectric constants, we showed that the pK(a) values of these internal residues are sensitive to the global stability of the protein; the shifts tend to be smaller in less stable forms of nuclease. This implies that the apparent dielectric constants reported by these internal ionizable groups are high because they reflect conformational reorganization coupled to their ionization. To detect this directly, acid-base titrations monitored with Trp fluorescence and near-UV and far-UV CD spectroscopy were performed on variants with Lys-66, Glu-66, or Asp-66 in background proteins with different stabilities. Conformational reorganization coupled to the ionization of the internal groups was spectroscopically detectable, especially in the less stable background proteins. The data show that to improve the accuracy of structure-based pK(a) calculations of internal groups the calculations will have to treat explicitly all structural reorganization coupled to ionization. The data also suggest a novel approach to mapping the folding free energy landscape of proteins by using internal ionizable groups to stabilize partially unfolded states.
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