Amino acids are the fundamental molecular units that link together to form proteins, the workhorses of all living cells. These molecules exist in three-dimensional space, and this spatial arrangement is important in biology. The concept of “handedness,” or chirality, means an amino acid can exist in two forms that are mirror images of one another, much like a person’s left and right hands. This geometric property influences how amino acids are recognized and utilized by enzymes and cellular machinery. The specific three-dimensional shape of an amino acid is defined by chemical nomenclature systems like R and S.
Understanding Molecular Handedness
The characteristic of handedness in amino acids stems from the alpha-carbon (\(\text{C}_{\alpha}\)), which acts as a stereocenter. This carbon atom is bonded to four distinct groups: a hydrogen atom (\(\text{H}\)), an amino group (\(\text{NH}_2\)), a carboxyl group (\(\text{COOH}\)), and a side chain (R-group). Because all four substituents are different, the alpha-carbon lacks a plane of symmetry, making the molecule chiral. A chiral molecule exists as a pair of non-superimposable mirror images called enantiomers. This distinction has biological consequences, as cellular receptors and enzymes are highly specific about the shape of the molecules they interact with.
The only standard amino acid that does not exhibit handedness is Glycine, because its R-group is simply another hydrogen atom. Since its alpha-carbon is bonded to two identical hydrogen atoms, it has a plane of symmetry and is considered achiral. For all other amino acids, an unambiguous designation of their spatial arrangement is necessary.
The Rules for R and S Assignment
The R/S system, or Cahn-Ingold-Prelog (CIP) nomenclature, provides an absolute method for describing the three-dimensional geometry of a stereocenter. This system prioritizes the four groups attached to the chiral carbon based on the atomic number of the atom directly connected to the stereocenter. The group with the highest atomic number receives the highest priority (1), and the lowest atomic number (usually hydrogen) receives the lowest priority (4). If a tie occurs, the rules dictate moving outward along the chain until a point of difference is found.
Once priorities are assigned, the molecule is mentally oriented so that the lowest priority group (4) is pointing away from the observer. The path is then traced from the highest priority group (1) to the second highest (2) and finally to the third highest (3). The direction of this path determines the final designation. If the path follows a clockwise direction, the stereocenter is assigned the configuration R (rectus, Latin for right). Conversely, if the path traced is counter-clockwise, the stereocenter is assigned the configuration S (sinister, Latin for left).
D vs L The Older Notation
The D/L system is a historical and relative method of stereochemical notation, primarily used in carbohydrate and amino acid chemistry. This system compares the molecule’s structure to a reference compound, glyceraldehyde, rather than relying on atomic priority ranking. The D and L designations are based on the relative arrangement of the amino group (\(\text{NH}_2\)) on the alpha-carbon when the molecule is drawn in a Fischer projection. For amino acids, the L-configuration is assigned if the amino group is positioned on the left side, and the D-configuration is assigned if it is on the right side.
It is important to understand that D and L do not relate to how the molecule rotates plane-polarized light, which is an optical property. For instance, L-amino acids can be either dextrorotatory (+) or levorotatory (-), showing no correlation between the two naming systems. The D/L system is considered a relative descriptor because it only specifies the relationship of the molecule to a chosen standard, not its absolute spatial geometry. Despite the R/S system providing an unambiguous description of absolute structure, the D/L system remains a common shorthand in biochemistry.
The Stereochemistry of Natural Amino Acids
The biological world exhibits a preference for one specific handedness of amino acids. Nearly all amino acids incorporated into proteins in living organisms are of the L-configuration. This L-form is the only type recognized by the cellular machinery responsible for protein synthesis. Therefore, when discussing common amino acids in nature, one is almost always referring to the L-enantiomer.
When the L-configuration is translated into the absolute R/S nomenclature, the L-form of most amino acids corresponds to the S-configuration. This consistency arises because the amino group (\(\text{NH}_2\)), the carboxyl group (\(\text{COOH}\)), and the side chain (R-group) fall into a consistent priority order under the CIP rules. The nitrogen atom in the amino group typically receives the highest priority (1), followed by the carbon of the carboxyl group (2), then the carbon of the R-group (3), with hydrogen being the lowest priority (4). The path from priority 1 to 2 to 3 for the L-configuration traces a counter-clockwise direction, resulting in the S designation.
There is one instructive exception among the common proteinogenic amino acids: Cysteine. The side chain of Cysteine contains a sulfur atom, which has a higher atomic number than the oxygen atoms in the carboxyl group. This difference elevates the priority of Cysteine’s side chain above the carboxyl group. Consequently, for L-Cysteine, the priority order is altered, and the trace follows a clockwise direction, making L-Cysteine an R-configured molecule. This highlights how the R/S system is strictly based on atomic number rules, meaning L-Cysteine is uniquely L and (R).