Amino acids

Absolute configuration at the $\alpha$ position

Understanding the absolute configuration of amino acids is fundamental to studying their stereochemical behavior in protein structures and biochemical reactions.

Absolute configuration describes the precise three-dimensional arrangement of substituents around a chiral center—typically the alpha carbon—in an amino acid. When assigning absolute configuration (R or S) to an amino acid, chemists use the Cahn-Ingold-Prelog priority rules to rank the four substituents around the alpha carbon.

In a typical amino acid, the alpha carbon is connected to an amino group, a carboxyl group, a hydrogen atom, and a variable side chain often referred to as R. After prioritizing these four groups, one examines their orientation around the chiral center to assign an R (“rectus”) or S (“sinister”) designation.

This S or R label is strictly about the spatial arrangement of the groups and remains distinct from the D or L notation, which is historically based on comparing the molecule’s projection to that of glyceraldehyde. Biologically, most naturally occurring amino acids are the L form and nearly all of them are S in their absolute configuration (when viewed according to the Cahn-Ingold-Prelog system).

Notable exceptions include glycine, which is achiral as its side chain is simply a second hydrogen, and cysteine, which typically has R configuration because the sulfur-containing side chain outranks the other groups in the priority rules.

Case 1: Priority of $N{H}_2>COOH>R$

For most amino acids, the substituent ranking is:

1. $N{H}_2$ (highest)
2. $COOH$
3. $R$
4. $H$ (lowest)

Viewed from the correct orientation (with the lowest-priority group—H—pointing away), this arrangement typically leads to an S absolute configuration when the amino acid is in its biologically common L form. Consequently:

• L = S
• D = R

Example:

• L-alanine normally ends up being S-alanine under CIP rules.

Here, the amino group outranks the carboxyl group, which in turn outranks the side chain. Since the side chain (for instance, a methyl group in alanine) has a lower atomic number priority than the carboxyl group, the final three-dimensional arrangement is S for the L enantiomer.

Case 2: Priority of $N{H}_2>R>COOH$

For cysteine, the sulfur-containing side chain outranks the carboxyl group because sulfur has a higher atomic number than the oxygen-based substituent in the carboxyl. Thus:

1. $N{H}_2$ (highest)
2. $R$ (the sulfur-containing side chain)
3. $COOH$
4. $H$ (lowest)

When you apply the CIP sequence rules to this ordering, the spatial arrangement for the L enantiomer becomes R instead of S. So:

• L = R
• D = S

Example:

• L-cysteine turns out to be R-cysteine.

This difference arises because the sulfur atom elevates the side chain above the carboxyl group in CIP priority. As a result, even though cysteine belongs to the same overall L category (based on its relationship to L-glyceraldehyde), its absolute configuration is R rather than S.

Why L vs. D does not always match S vs. R

• L / D notation refers to how the molecule lines up with the reference standard of glyceraldehyde and does not directly hinge on atomic priorities.
• S / R notation is purely about substituent ranking around the chiral center as per the Cahn-Ingold-Prelog rules.

In most amino acids, the L form corresponds to the S configuration (Case 1), but cysteine (Case 2) is the classic example where the L form is actually R by CIP rules because of the higher priority sulfur substituent.

Amino acids as dipolar ions

Amino acids can exist as dipolar ions, commonly referred to as zwitterions, because each molecule carries both a positive and a negative charge under typical physiological conditions. More specifically, an amino acid contains an amino group (–$N{H}_2$) and a carboxyl group (–$COOH$). In an acidic environment, the amino group gains a proton, becoming –$N{H}_3$⁺, while the carboxyl group often donates a proton, turning into –$CO{O}^{-}$.

Consequently, the same molecule bears both a positively charged group (on nitrogen) and a negatively charged group (on oxygen) at the same time. This arrangement stabilizes the overall structure and influences how:

• Amino acids dissolve
• Interact with charged molecules
• Fold into larger proteins.

The exact pH value at which an amino acid predominantly assumes its dipolar form varies, based on factors such as side-chain properties and the pKa values of the functional groups. However, in biological systems near neutral pH, most amino acids exist largely in this zwitterionic state, affecting how they behave in aqueous solutions and how they bind to enzymes or other biomolecules.

Amino acid classifications

Acidic or basic

• Due to their dual functional groups, the carboxyl group (–$COOH$) and the amino group (–$N{H}_2$), amino acids can act as both acids and bases. In an acidic environment, the amino group can accept a proton, becoming –$N{H}_3+$, while in a more basic setting, the carboxyl group can lose a proton, forming –$CO{O}^{-}$. These reversible proton transfers allow amino acids to buffer pH changes and exhibit amphoteric behavior.

Hydrophobic or hydrophilic

• Beyond their acidic and basic properties, amino acids can also be classified based on the nature of their side chains, which can make them hydrophobic or hydrophilic.

Hydrophobic amino acids typically possess nonpolar side chains consisting mostly of carbon and hydrogen, causing them to avoid water and favor interactions with other nonpolar surfaces. In contrast, hydrophilic amino acids have polar or charged side chains that readily form hydrogen bonds or electrostatic interactions with water. This distinction in side-chain polarity strongly influences:

• How amino acids orient themselves in proteins
• How they cluster or repel each other
• How they shape overall protein folding and function.

Amino acid reactions

Sulfur linkage for cysteine and cystine

• Cysteine, one of the sulfur-containing amino acids, features a thiol group ($–SH$) in its side chain. When two cysteine residues come into close proximity within a polypeptide or between different polypeptide chains, their sulfur atoms can form a disulfide bond, yielding cystine. This disulfide linkage ($–S–S–$) plays a crucial stabilizing role in the three-dimensional structure of proteins, helping maintain the protein’s overall shape and ensuring its functional integrity.

Peptide linkage: polypeptides and proteins

• Besides sulfur linkages, peptide bonds are also fundamental to amino acid assembly. When the carboxyl end (–$COOH$) of one amino acid reacts with the amino end (–$N{H}_2$) of another, a peptide linkage is formed, releasing a molecule of water in the process. This condensation reaction repeatedly joins amino acids into longer chains called polypeptides. Depending on factors such as length and complexity, polypeptides can either remain relatively short or fold into larger, more elaborate assemblies known as proteins. Within proteins, the specific sequence of amino acids (the primary structure) and the subsequent folding and shaping (secondary, tertiary, and sometimes quaternary structures) determine the protein’s function, stability, and interactions with other molecules.

Hydrolysis

• Hydrolysis of amino acids, in the context of peptide or polypeptide breakdown, involves cleaving the peptide bond—the chemical link formed between the carboxyl group of one amino acid and the amino group of another. This reaction can occur through various methods: acid or base treatment in a laboratory setting, or via specialized enzymes (often called proteases) in biological systems. Regardless of the mode, the result is that water molecules intervene to break the bond, generating shorter segments—such as dipeptides or tripeptides—or ultimately releasing the individual amino acids themselves. In living organisms, this controlled process is essential for protein digestion and turnover, allowing cells to recycle or repurpose amino acids for new protein synthesis or energy production.

If we denote a compound as AB, where A and B represent atoms or groups, and water is expressed as HOH, the process of hydrolysis can be depicted by the reversible chemical equation:

$$AB+HOH\rightleftharpoons AH+BOH$$