Absolute configuration at the α position

Amino acids are the building blocks of proteins.

There are 20 amino acids encoded by the standard human genetic code. 10 of the amino acids are considered essential amino acids for humans as our bodies cannot produce them; they must be obtained from the diet. However, knowledge of which amino acids are essential is beyond the scope of what you need to know.

Each amino acid has the same fundamental structure, which consists of a central carbon atom, also known as the alpha (α) carbon, bonded to an amino group (-NH₂), a carboxyl group (-COOH), hydrogen atom, and a unique side chain (-R). Because the alpha carbon is bonded to four unique substituents, each amino acid is chiral (with the exception of glycine, which has two indistinguishable hydrogen atoms on the alpha carbon). Every chiral amino acid has a relative configuration of L, and all but one chiral amino acid has an absolute configuration of S at the alpha carbon. The exception is cysteine, which has an absolute configuration of R at the alpha carbon.

The varying side chain (it’s “R group”) is what gives each amino acid it’s unique properties, influencing it’s size, polarity, and charge, among other things. For instance, the R group of serine contains a hydroxyl functional group which is capable of hydrogen bonding, increasing the solubility of serine in water.

Amino acids as dipolar ions

The amino group of an amino acid is a base which is typically protonated in the aqueous environment of the cell, giving the N-terminus a positive charge. The carboxylic acid functional group of an amino acid is an acid which is typically deprotonated in the aqueous environment of the cell, giving the C-terminus a negative charge. Since both the amino group and the carboxyl group are ionized under physiological conditions, they are often drawn as -NH₃⁺ and -COO^–, respectively. Only the acidic and basic amino acids feature any other ionizable residues. Therefore, because they feature a plus one and minus one charge at physiological pH, most of the amino acids are zwitterions (ions whose charges cancel out, producing a molecule with neutral charge).

Classifications

Amino acids with acidic residues have an additional negative charge at physiological pH, while amino acids with basic residues have an additional positive charge at physiological pH. Therefore, the acidic amino acids are typically negatively charged (anionic), while the basic amino acids are typically positively charged (cationic). Amino acids are not always kept under physiological conditions, where pH is about 7.4. Changes in the pH of their environment can affect their charge. When amino acids are kept under low pH conditions, more of the residues will be protonated, resulting in a net positive charge. When amino acids are kept under high pH conditions, more of the residues will be deprotonated, resulting in a net negative charge.

 

We will quickly overview some of the most important cases where an amino acid side chain gives that amino acid a unique property; memorize each side chain and be ready to apply their properties on test day.

1. Side chains with charges can either interact attractively when the side chains are oppositely charged (e.g. lysine and aspartic acid) or repulsively when the side chains have the same charge (e.g. lysine and arginine). An attractive charge interaction will often stabilize a protein whereas a repulsive interaction will often destabilize a protein; however, this is not always the case, and you must be ready to pay careful attention to passage information on test day.

2. Some amino acid side chains naturally destabilize proteins with a helical structure. Specifically, if glycine or proline are added into a protein, they will often destabilize (break down) the local structure.

3. There are three amino acids whose side groups are most often targets of phosphorylation: serine, threonine, and tyrosine. Phosphorylation is the addition of a negatively charged phosphate to a molecule, which often changes the structure or function of that molecule. Notice that each of these three amino acids features a hydroxyl function group.

4. Cysteine is sometimes able to produce covalent disulfide bonds with other cysteine residues, holding together the subunits of a polypeptide.

5. Perhaps most importantly, amino acids with non-polar side chains are more hydrophobic (water-fearing), and will tend to try and aggregate together in ways that minimize their contact with water, while amino acids with polar or charged side chains are more hydrophilic (water-loving), and favorably interact with water.

Sulfur linkage for cysteine and cystine

A covalent disulfide bond (sulfur linkage) can form between the sulfur-containing R groups of two cysteine molecules (called sulfhydryl groups). Disulfide bonds between cysteine residues can affect protein folding and stability. Disulfide bonds form between cysteine residues under oxidizing (high pH) conditions. Disulfide bonds can be broken under reducing (low pH) conditions.

Peptide linkage: polypeptides and proteins

A peptide is a molecule composed of two or more amino acids. The bond connecting together the two amino acids is a peptide bond. It occurs when the amino group of one amino acid nucleophilically attacks the carboxyl group carbon of another amino acid, linking the two molecules together and releasing a water molecule. In the final product, the amino and carboxyl group have been transformed into an amide functional group (carbon double bonded to an oxygen and single bonded to a nitrogen). Because this reaction releases a water molecule, it is a specific example of a condensation reaction. Peptide bond formation is endergonic (a process which requires energy), the energy for which typically comes from ATP.

Hydrolysis

Long chain polypeptides can be formed by linking many amino acids to each other via peptide bonds. The peptide bond can only be broken by hydrolysis, where the bonds are cleaved with the addition of a water molecule.

Because this reaction is the reverse of peptide bond formation, it is exergonic (releases energy) and occurs spontaneously. Despite the fact that peptide bonds will spontaneously want to break down, the activation energy for this reaction is high enough that peptide bonds are metastable and will break down very slowly. Living organisms have enzymes that are capable of both forming and breaking peptide bonds.

Practice Questions

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Key Points

• Amino acids are the monomers that make up proteins.

• Each amino acid has the same fundamental structure, which consists of a central carbon atom, also known as the alpha (α) carbon, bonded to an amino group (-NH₂), a carboxyl group (-COOH), a hydrogen atom, and a side chain (R group).

• Amino acids with L absolute configuration are more common in nature and are the only type found in proteins.

• The chemical composition of the side chain determines the characteristics of the amino acid (hydrophilic or hydrophobic, basic or acidic, etc.).

• Amino acids can be made through the Gabriel or Strecker synthesis.

• Amino acids are covalently bound by a peptide bond – carboxyl group of one to amino group of the other – which will release water.

• Hydrolysis (addition of water) can break a peptide bond.

• Two cysteines in a polypeptide can interact with each other to form a disulfide bond

Key Terms

• amino acid: monomer of proteins

• N-terminus: one of the four functional groups bonded to each amino acid’s alpha carbon; an amino group which is positively charged under physiological conditions.

• C-terminus: one of the four functional groups bonded to each amino acid’s alpha carbon; a carboxylic acid group which is negatively charged under physiological conditions.

• cationic: a positively charged ion

• anionic: a negatively charged ion

• zwitterionic: A molecule with functional groups of which at least one has a positive and one has a negative electrical charge; the net charge of the entire molecule is zero

• phosphorylation: the addition of a phosphate group to a molecule

• cysteine: a sulfur-containing amino acid

• condensation: any reaction where two molecules combine to form a single molecule, often releasing a water molecule as a byproduct

• disulfide bond(also referred to as an S-S bond, disulfide bridge, or sulfur linkage): a covalent bond derived from two cysteine thiol groups

• peptide bond(also called peptide linkage): a chemical bond formed between two amino acids when the amino group of one amino acid attacks the carboxyl group of another, releasing a molecule of water. This is an endergonic reaction.

• hydrolysis: any reaction where a bond is broken due to the addition of water