Buried charges detection

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This page is under development. Eric Martz 20:04, 8 February 2021 (UTC)

The four common amino acids whose sidechains are fully charged from pH 5 to 9, in the absence of environmental effects, are Arg, Asp, Glu, & Lys[1]. Although the highly hydrophilic sidechains of these amino acids tend to be on the surfaces of soluble proteins, they are often found buried[1]. In fact, on average, about half of the charged sidechain oxygens or nitrogens of Arg, Asp, and Glu are buried, while about one third of Lys sidechain nitrogens are buried[1][2]. Buried ionizable sidechain pKa's shift due to dehydration, net charge of the protein, hydrogen bonds, and other environmental influences[1][3]. This may leave them uncharged, or charged over a wider range of pH's than would be expected from their intrinsic pKa's.

Protein Stability

Buried ionizable sidechains engaged in multiple hydrogen bonds, or in salt bridges, contribute to protein stability, while those lacking such interactions contribute to instability[1][4]. Thermophilic proteins often have fewer buried ionizable sidechains[4]. Stability does not increase with protein size[1]. The independence of protein stability vs. size appears related to burial of more ionizable sidechains that are not hydrogen bonded in large proteins. Proteins with <100 residues have on average 1.9 buried ionizable sidechains, while those with >300 residues average 4.9/100 residues[1].

Definitions of "Buried"

The most common definition of buried is based on the loss of solvent-accessible surface area (SAS) of an amino acid in the folded protein, compared to its surface area in an unfolded state, such as when it is the middle residue of a tripeptide[4]. Kajander et al.[4] defined charged groups with <5% SAS as fully buried, and those with 5-25% SAS as partially buried.

Many buried ionizable sidechains form salt bridges with nearby opposite charges, and others form usually multiple hydrogen bonds. Few have neither[4]. Some, of course, may be involved in a functional site.

By the SAS definition, charged groups may be buried, yet likely exposed to solvent some of the time due to thermal motion and their proximity to the molecular surface. An example is Lys191 in hemocyanin 1LLA. Its sidechain amino is buried, but some of the methylene (-CH2) sidechain groups are partly exposed on the surface[4].

References Cited

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Pace CN, Grimsley GR, Scholtz JM. Protein ionizable groups: pK values and their contribution to protein stability and solubility. J Biol Chem. 2009 May 15;284(20):13285-9. doi: 10.1074/jbc.R800080200. Epub 2009 , Jan 21. PMID:19164280 doi:http://dx.doi.org/10.1074/jbc.R800080200
  2. ↑ Lesser GJ, Rose GD. Hydrophobicity of amino acid subgroups in proteins. Proteins. 1990;8(1):6-13. doi: 10.1002/prot.340080104. PMID:2217164 doi:http://dx.doi.org/10.1002/prot.340080104
  3. ↑ Thurlkill RL, Grimsley GR, Scholtz JM, Pace CN. Hydrogen bonding markedly reduces the pK of buried carboxyl groups in proteins. J Mol Biol. 2006 Sep 22;362(3):594-604. doi: 10.1016/j.jmb.2006.07.056. Epub 2006, Jul 29. PMID:16934292 doi:http://dx.doi.org/10.1016/j.jmb.2006.07.056
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Kajander T, Kahn PC, Passila SH, Cohen DC, Lehtio L, Adolfsen W, Warwicker J, Schell U, Goldman A. Buried charged surface in proteins. Structure. 2000 Nov 15;8(11):1203-14. PMID:11080642

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