Lys

The side chain of Lys is a flexible hydrophobic chain of four methylene groups capped by an amino group:

The amino group ionizes with an intrinsic pKa value of about 11.1, so it is ionized under most physiological conditions. The ionized form is unreactive chemically, but there is always a finite fraction of nonionized amino groups, which are potent nucleophiles. Consequently, the amino groups of Lys residues readily undergo a typical wide variety of acylation, alkylation, arylation, and amidination reactions (see Amino Groups). These reactions can be used to measure the number of Lys residues in a protein (see Counting Residues and Trinitrobenzene Sulfonic Acid).

The ionized amino groups of Lys residues in protein structures are nearly always exposed to the solvent, with the entire side chain typically exposed to the solvent and flexible, when they have relaxation times in the nanosecond range. Of secondary structures, Lys residues occur most frequently in a-helices; they also favor the helical conformation in model peptides. Virtually no Lys residues are buried within the interiors of proteins. They are occasionally used to attach prosthetic groups to proteins, such as the Schiff Base attachment of pyridoxal phosphate to some enzymes. In an important post-translational modification, Lys residues of collagens in the sequence -Xaa-Lys-Gly- are hydroxylated on the d carbon by the enzyme lysyl 5-hydroxylase.

Proteinases frequently cleave polypeptide chains adjacent to Lys residues, as in the processing of pro-hormones, such as pro-insulin, at pairs of basic residues.

Arg

Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability

Several properties of Arg residues suggest that they would be better adapted to high temperatures than Lys residues: the Arg δ-guanido moiety has a reduced chemical reactivity due to its high pK_a and its resonance stabilization. The δ-guanido moiety provides more surface area for charged interactions than the Lys amino group does.

Figure4 illustrates the ability of Arg to participate in multiple noncovalent interactions. Because the Arg side chain contains one fewer methylene group than Lys, it has the potential to develop less unfavorable contacts with the solvent.

Last, because its pK_a (approximately 12) is 1 unit above that of Lys (11.1), Arg more easily maintains ion pairs and a net positive charge at elevated temperatures (pK_a values drop as the temperature increases) (252, 354).

The average Arg/Lys ratios in the protein pools of the mesophiles and hyperthermophiles listed in Table ​Table4 (0.73 ± 0.37 and 0.87 ± 0.60, respectively) are associated with large standard deviations. (Among hyperthermophiles, Arg/Lys ratios vary from 0.52 in Aquifex aeolicus proteins to 2.19 in Aeropyrum pernix proteins.) These results suggest that if an increased Arg content is indeed stabilizing, this mechanism is not universally used among hyperthermophiles.

Stereo view of the ion pair between Arg19 and Asp111 in S. solfataricus indole-3-glycerol phosphate synthase. The Arg19 guanidinium group also forms a cation-π interaction with the Tyr93 π system and two H bonds with Thr84. Reprinted from reference 185 with permission of the publisher.



Arginine residues as stabilizing elements in proteins

Site-specific substitutions of arginine for lysine in the thermostable D-xylose isomerase (XI) from Actinoplanes missouriensis are shown to impart significant heat stability enhancement in the presence of sugar substrates most probably by interfering with nonenzymatic glycation. The same substitutions are also found to increase heat stability in the absence of any sugar derivatives, where a mechanism based on prevention of glycation can no longer be invoked. This rather conservative substitution is moreover shown to improve thermostability in two other structurally unrelated proteins, human copper, zinc-superoxide dismutase (CuZnSOD) and D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Bacillus subtilis. The stabilizing effect of Lys----Arg substitutions is rationalized on the basis of a detailed analysis of the crystal structures of wild-type XI and of engineered variants with Lys----Arg substitution at four distinct locations, residues 253, 309, 319, and 323. Molecular model building analysis of the structures of wild-type and mutant CuZnSOD (K9R) and GAPDH (G281K and G281R) is used to explain the observed stability enhancement in these proteins. In addition to demonstrating that even thermostable proteins can lend themselves to further stability improvement, our findings provide direct evidence that arginine residues are important stabilizing elements in proteins. Moreover, the stabilizing role of electrostatic interactions, particularly between subunits in oligomeric proteins, is documented.


A structural role for arginine in proteins: multiple hydrogen bonds to backbone carbonyl oxygens.

We propose that arginine side chains often play a previously unappreciated general structural role in the maintenance of tertiary structure in proteins, wherein the positively charged guanidinium group forms multiple hydrogen bonds to backbone carbonyl oxygens. Using as a criterion for a "structural" arginine one that forms 4 or more hydrogen bonds to 3 or more backbone carbonyl oxygens, we have used molecular graphics to locate arginines of interest in 4 proteins: Arg 180 in Thermus thermophilus manganese superoxide dismutase, Arg 254 in human carbonic anhydrase II, Arg 31 in Streptomyces rubiginosus xylose isomerase, and Arg 313 in Rhodospirillum rubrum ribulose-1,5-bisphosphate carboxylase/oxygenase. Arg 180 helps to mold the active site channel of superoxide dismutase, whereas in each of the other enzymes the structural arginine is buried in the "mantle" (i.e., inside, but near the surface) of the protein interior well removed from the active site, where it makes 5 hydrogen bonds to 4 backbone carbonyl oxygens. Using a more relaxed criterion of 3 or more hydrogen bonds to 2 or more backbone carbonyl oxygens, arginines that play a potentially important structural role were found in yeast enolase, Bacillus stearothermophilus glyceraldehyde-3-phosphate dehydrogenase, bacteriophage T4 and human lysozymes, Enteromorpha prolifera plastocyanin, HIV-1 protease, Trypanosoma brucei brucei and yeast triosephosphate isomerases, and Escherichia coli trp aporepressor (but not trp repressor or the trp repressor/operator complex)



ps.
moiety 一半, (两个组成部分中的一)部分

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5. Draw the predominant form of arginine at pH 7.4 and 12. Important pK's for the functional groups in this amino acid are α-carboxyl=2, δ-guanido=12, α-amino=9. What is the ratio of conjugate base/acid for the δ-guanido group in arginine at pH 7.4 and 12?






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The Arg side chain consists of three nonpolar methylene groups and the strongly basic d-guanido group:


With a p value usually of about 12, the guanido group is ionized over the entire pH range in which proteins exist naturally. The ionized guanido group is planar as a result of resonance:

and the positive charge is effectively distributed over the entire group. In the protonated form, the guanido group is unreactive, and only very small fractions of the nonionized form are present at physiological pH values. The guanido groups of Arg residues are almost invariably at the surfaces of native protein structures, and virtually no Arg residues are fully buried, but the nonpolar part of the side chain, and the adjoining polypeptide backbone, are frequently buried within the interior. Arg residues favor the alpha-helical conformation in model peptides and also occur most frequently in that secondary structure in folded protein structures.

Salt-bridge angle

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salt bridge : normal define ( short-range)

long rang salt-bridge : Centroids of the side-chain charged
                                    group is greater than 4 A


A pair of oppositely charged residues, Asp or Glu with Arg, His, or Lys, is considered an ion pair. The geometrical orientation of the side-chain charged groups in the ion-pairing residues with respect to each other is characterized in terms of
1) the distance (r) between the side-chain charged group centroids and
2) the angular orientation (θ) of the side-chain charged groups in the two ion-pairing residues.
This is the angle between two unit vectors. Each unit vector joins a C^α atom and a side-chain charged group centroid in a charged residue. Fig. 1 presents a schematic diagram.





Figure 1. A schematic diagram characterizing geometrical orientation of the side-chain charged residues in an ion pair. Ion pair geometry can be measured in terms of r and θ. r is the distance in angstroms between the centroids, C1 and C2, of the side-chain charged groups in the ion-pairing residues 1 and 2. θ, in degrees, is the angle between two unit vectors C1^αC1 and C2^αC2. Note that we actually take the supplemental angle.


 

Figure 3. The spatial orientations of side-chain charged groups in 1174 ion pairs in 14 NMR conformer ensembles. The number of unique ion pairs is 22. The ion pair types are color coded. Salt bridges are in blue, N_O bridges in green, and longer range ion pairs in red. 

The geometry of an ion pair can be characterized in terms of distance between its side-chain charged group centroids (r (Å)) and angular orientation of its side-chain charged groups (θ (°)). In this polar plot, radii of the concentric circles represent different r (Å) values. 

The dotted lines connecting the circles denote different θ (°) values. Additional details are given in Materials and Methods. Most of the ion pairs with r ≤ 5 Å are stabilizing. In contrast, most of the ion pairs with r > 5 Å are destabilizing.


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Salt Bridge Stability in Monomeric Proteins

The angular orientation of the side-chain charged groups in the two salt-bridging residues is computed as the angle between two unit vectors. Each unit vector joins a Ca atom and a side-chain charged group centroid in a salt- bridging residue. 

The angle between the vectors that join the Ca atoms and the side-chain charged group centroids is 46.3 度 , resulting in a very good bridge geometry.

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To resolve these different findings, we performed analysis of the geometries of salt bridges in a representative set of structures from the PDB and found that over 87% of all complex salt bridges anchored by Arg/Lys have a geometry such that the angle formed by their Cα atoms, Θ, is < 90°.

This preferred geometry is observed in the two reported instances when the energetics of complex salt bridge formation is cooperative, while in the reported anti-cooperative complex salt bridge, Θ is close to 160°. Based on these observations, we hypothesized that complex salt bridges are cooperative for Θ < 90° and anti-cooperative for 90° < Θ < 180°.






Cartoon representation of the spatial arrangement of complex salt bridges


 

Cartoon illustrating a possible source of cooperativity in complex salt bridges