Four side chains are charged at physiological pH values. The charges occur at the ends of the side chains, away from the backbone. Aspartate and glutamate are negatively charged; lysine and arginine are positively charged. The methylene groups between the charged functional group and the backbone are nonpolar.

The Acidic Residues: Asp and Glu

The side chains of aspartate and glutamate differ only in having one and two methylene groups, respectively. The carboxyl groups of the side chains have pK values of 3.9 (Asp) and 4.3 (Glu), so these side chains are ionized at pH 7.

The Basic Residues: Lys and Arg

The side chain of lysine is a hydrophobic chain of four methylene groups (the β, γ, δ, and ε carbon atoms) capped by an ε-amino group. The ε-amino group has a pK value near 11, so it is ionized under most physiological conditions.

The Lys side chain with its charged ε-amino group usually projects into the aqueous phase. There it is free to move in three dimensions because of free rotation around the C–C bonds. What is better energetically: to expose the lysine side chain completely, or to bury its hydrophobic part and expose only the charged ⁺NH₃ group? We'll return to this provocative question later we discuss the role of side chain entropy in protein folding.

The side chain of arginine consists of three nonpolar methylene groups and the δ-guanidino group. The guanidino group has a pK value of about 13, so it is ionized over the entire pH range in which proteins exist naturally. The ionized guanidino group or guanidinium ion is planar as a result of resonance.

The guanidinium ion is composed of four trigonal (sp²-hybridized) atoms -- three nitrogens and a central carbon -- in the shape of a Y. Each atom has one p orbital. The carbon p orbital has no nonbonding electrons and lies perpendicular to the plane of the C–N bonds. It overlaps the three filled p orbitals of the nitrogen atoms. Six π electrons fill the three π molecular orbitals of the lowest energy. The positive charge is delocalized over the three nitrogens and the central carbon, stabilizing the guanidinium ion. The delocalization energy is greater than that for benzene and prevents the guanidinium carbocation from reacting with nucleophiles.

The α carbon is colored dark gray. The guanidino group is always positively charged. Toggle spacefilling model.

Isolate the guanidinium ion.

What a beautiful molecule -- it's planar, all C–N bonds are equal, and all bond angles are perfectly 120°. Based on these observations, describe the electronic structure of the guanidinium cation. How do the nitrogen atoms stabilize the carbocation?

Show Answer

The carbon atom has only six electrons. It is sp² hybridized and is bonded to three nitrogen atoms, with bond angles of exactly 120°. The three nitrogen atoms are also sp² hybridized. The filled p orbitals can overlap with the empty p orbital of the carbon atom. Therefore, the positive charge is not confined to the carbon atom but is delocalized over the four sp² hybridized atoms. The ability to spread the positive charge over four atoms rather than concentrating it on just one atom accounts for the stability of the guanidinium ion, making it the "world's most stable carbocation."