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Peptide Bonds

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The Basics of Peptide Bonds

A peptide bond is a type of covalent bond that joins two amino acids. It forms when the carboxyl group of one amino acid reacts with the amino group of another, releasing a molecule of water—a process known as a condensation reaction. This reaction creates a CO–NH linkage between the carbon atom of the carboxyl group and the nitrogen atom of the amino group. This bond is called a peptide bond and is a specific type of amide bond, since the resulting molecule shares the structure commonly found in amides.

Peptide Bond Formation

For a peptide bond to form, the amino acids must be positioned so that the carboxylic acid group of one amino acid can react with the amine group of another. At its simplest, this can be visualized as two individual amino acids joining through a peptide bond to create a dipeptide, which is the smallest type of peptide (made up of just two amino acids).

From there, additional amino acids can be added in sequence to build longer chains:

  • Chains of about 50 amino acids or fewer are typically called peptides.
  • Chains of roughly 50 to 100 amino acids are often called polypeptides.
  • Chains of more than 100 amino acids are usually considered proteins.

For a more detailed comparison of peptides, polypeptides, and proteins, you can refer to resources that specifically discuss “Peptides vs. Proteins.”

Peptide bonds can be broken by hydrolysis, which is a chemical reaction in which water helps to split a compound. Although the spontaneous reaction is relatively slow, peptide bonds in peptides, polypeptides, and proteins are considered metastable. Over time and in the presence of water, they can be cleaved, releasing about 10 kJ/mol of free energy per peptide bond. Peptide bonds also have characteristic optical properties. They absorb light in the ultraviolet range, with an absorption maximum between approximately 190 and 230 nm.

In living systems, enzymes play a key role in both forming and breaking peptide bonds. Many biologically active substances such as hormones, antibiotics, antitumor agents, and neurotransmitters, are peptides or peptide-derived structures, although many of these are large enough to also be classified as proteins.

Anatomy of a Peptide Bond

X-ray diffraction studies of small peptides have revealed important details about the physical structure of peptide bonds. These studies show that peptide bonds are generally rigid and planar. This rigidity arises from resonance within the amide group. The nitrogen atom in the amide can share its lone pair of electrons with the carbonyl system, allowing partial electron delocalization between the nitrogen and the carbonyl oxygen.

Because of this resonance:

  • The N–C (amide) bond in the peptide backbone is shorter than a typical N–Cα single bond.
  • The C=O bond in the peptide is slightly longer than a standard carbonyl double bond.

Within a peptide, the carbonyl oxygen and the amide hydrogen usually adopt a trans configuration rather than a cis configuration. The trans arrangement is energetically favored because it reduces steric clashes between groups attached to the alpha carbons on either side of the peptide bond.

The Polarity of the Peptide Bond

Ordinarily, one might expect free rotation around a single bond between a carbonyl carbon and an amide nitrogen. However, in the peptide bond this rotation is restricted. The amide nitrogen has a lone pair of electrons adjacent to the carbon–oxygen double bond, enabling a resonance structure in which a partial double bond forms between the carbon and nitrogen.

In this resonance form:

  • The carbon–nitrogen bond has partial double-bond character.
  • The oxygen carries a partial negative charge.
  • The nitrogen carries a partial positive charge.

As a result, the true peptide bond is best described as a hybrid of the single-bond and double-bond resonance structures, with roughly 40 percent double-bond character. This partial double-bond nature is what makes the peptide bond relatively rigid and limits rotation around that bond.

The unequal distribution of charge creates a permanent dipole across the peptide bond. Quantitatively, the oxygen atom carries an approximate charge of –0.28, while the nitrogen carries an approximate charge of +0.28. This polarity affects how peptides interact with their environment, including how they align in proteins, form hydrogen bonds, and participate in secondary structure elements such as alpha helices and beta sheets.