I am curious whether the pKa of a charged side chain on the surface of a protein can be influenced by the charged state of nearby amino acids.
My hypothesis suggests that, in comparing Figure 1A and 1B, 1B would be more stable energetically due to reducing repulsion from the charge. Therefore, I propose that this could lead to an increase in pKa, as illustrated in Figure 2.
Is my hypothesis scientifically valid, and are there any literature references supporting it?
Dear Daeseong Kim Sure, it is well-known that pKa values can be shifted significantly by for example neighboring charged groups in complex molecular structures.
See for example:
Harris, T. K., & Turner, G. J. (2002). Structural basis of perturbed pKa values of catalytic groups in enzyme active sites. IUBMB life, 53(2), 85-98.
Harms MJ, Castañeda CA, Schlessman JL, Sue GR, Isom DG, Cannon BR, García-Moreno E B. The pK(a) values of acidic and basic residues buried at the same internal location in a protein are governed by different factors. J Mol Biol. 2009 May 29;389(1):34-47. doi: 10.1016/j.jmb.2009.03.039. Epub 2009 Mar 24. PMID: 19324049; PMCID: PMC3373015.
Panahi, A., & Brooks III, C. L. (2015). Membrane Environment Modulates the p K a Values of Transmembrane Helices. The Journal of Physical Chemistry B, 119(13), 4601-4607.
Peng Y, Alexov E. Computational investigation of proton transfer, pKa shifts and pH-optimum of protein-DNA and protein-RNA complexes. Proteins. 2017 Feb;85(2):282-295. doi: 10.1002/prot.25221. Epub 2017 Jan 5. PMID: 27936518; PMCID: PMC9843452.
Best regards.
Thank you so much for your response. The information I was looking for was in the references you provided. I really appreciate it!!
Yes, there is some specific term for this phenomena but I remember what it is called. Something to do with neighboring charge residues.
The majority of protein crystal structures are about 2 - 3 angstrom resolution. At a good resolution (resolution > 2 angstroms), it is not possible to see the protons on any atoms of a protein crystal structure. However, atoms are added algorithmically by X-ray refinement software and side chains of proteins are twisted and rotated to assure optimal hydrogen bonding. At a resolution of 1 angstrom, it is possible to see the majority or all of the protons of all the side chains in a protein crystal from the electron density. Normally this is difficult, but if if your protein is lysozyme, the crystals are just perfect and the resolution is just great.
For instance, all of the protons in this crystal structure are known to pretty much 100% certainty because the resolution of the crystal structure is 0.65 Angstroms.
https://www.rcsb.org/structure/2VB1
The pKa of lysine that is solvent exposed is probably about 10. Therefore at pH 7, lysine is protonated with a positive charged. The pKa of arginine is at least 12 and is thus protonated at nearly every pH. But if a lysine residue neighbors an arginine residue which are nearly always positively charged, the lysine residue may have a pKa < 7 and thus not be protonated and have a pair of electrons. These electrons of the lysine can attack a C=O bond in a ketone or aldehyde of a molecule to form a covalent linkage. This happens in pretty much every single enzyme which is covalently modified with pyridoxal phosphate (active form of vitamin B6) which is a huge number of enzymes, a textbooks worth number of enzymes. The reactive lysine can be covalently bound to a small molecule with a ketone or aldehyde functional group. The reactive lysine can be found attached tot he small molecule with mass spectrometry, and now the pKa of the lysine being less than 7 is no longer crystallographer's guess.
The reactive lysine is nearly always near a positively charged residue.
- Badges
- Science topic
- Similar topics
- Biological Science
- Biochemistry
- Enzymology
- Enzymes