This contrasts with Lys where the charge is largely focused on the terminal aliphatic amino group and the side chain is readily deprotonated in proteins 1. The very high pKa of Arg results from delocalization of the positive charge within the π-bonded system of the side chain guanidinium ion so stable is the guanidinium that the Arg side chain remains protonated when partially buried within protein structures or membranes 3, 4. These amino acids have profound roles in protein structure and function that involve electrostatic interactions and protein solvation. Lysine and arginine are the two positively charged amino acids in proteins that have high aqueous pKa’s (~10.5 for Lys 1 and ~13.8 for Arg 2) indicating a strong propensity to carry charge at physiological pH. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations and likely underlie the preference for arginine as a mobile charge carrier in VSD. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain.

The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. This arginine preference may result from the unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. This form of an amino acid is called the zwitterion form (German for 'double ion').Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. Thus, amino acids usually have both a positive charge on the amine group and a negative charge on the acid group. Similarly, the acid group has a relatively low pKa, so around pH 7 it will tend to donate its proton to water, becoming negatively charged. The amine group of an amino acid has a relatively high pKa, so at physiological pH (about 7), it will tend to bind a proton, becoming positively charged. The side chain is usually represented by an R. The other groups are bonded to the a carbon On the structure of valine (Val) at the right, try clicking on the following groups: The 20 amino acids are sorted into 4 groups, hydrophobic, polar but uncharged, basic, and acidic, depending on the nature of their side chains (R groups). For example, Val is the abbreviation for valine. All 20 amino acids have three-letter abbreviations for their names. The structure of an amino acid is shown at right (R is a generic letter used to take the place of the side chain). An amino acid is a carbon atom (called the a carbon) bonded to a hydrogen atom, an amine group, a carboxylic acid group, and one of 20 different side chains.

Positively charged amino acids