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Peptide Bonds
Biochem 4511
Figures: Essentials of Biochemistry, 3rd Ed
...
, Moran et al
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, Nelson & Cox
Fundamentals of Biochemistry 2nd Ed
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Proteins as Macromolecules
•  1840s: earthworm blood on a slide forms crystals
•  Crystals of hemoglobin were grown from several
hundred species and had different properties

•  Results: proteins are (relatively) pure
substances with a distinct shape
•  Different species are measurably chemical
distinct!

Peptide Bond Formation
•  Peptide (amide) bond
formed by the
condensation of two
amino acids and the
release of a water
molecule
•  When drawing
peptides using Fischer
projections, use the
AC linear format to
maintain proper
stereochemistry

Peptide Bond Formation
•  Practice drawing the peptide TEST using the amino acid
line structure drawing rules you have learned:

Peptide Bond Resonance

•  Partial double bond character maintains planarity of
peptide (amide) bonds

Peptide Bond Planarity

•  Partial double bond character maintains planarity of
peptide (amide) bonds
•  As a result, protein backbone rotations are similar to
sheets of paper

Amides: Planarity

•  In extended linear form, side chains are on alternating sides
due to stereochemistry
•  This is the most convenient way to “draw” peptides, but this
structure is not extensively found in folded proteins

Amides: cis vs trans

•  Trans is energetically favored due to steric clash of side
chains in cis conformation
•  The severity of this effect will depend on the side chain
•  Do you think glycine may commonly be found in the cis
conformation?

Proline: cis vs trans

•  Due to the ring structure of proline, cis and trans are
energetically similar for X-Pro (often ~30% cis)

Peptide Drawing Rules
• 
• 
• 
• 

Always written N to C
If one-letter codes, all capital letters
If three-letter codes, first letter capitalized
Termini are sometimes specified

PEPTIDE
H2N-PEPTIDE-COOH
ProGluProThrIleAspGlu
H2N-Pro-Glu-Pro-Thr-Ile-Asp-Glu-OH
Proline-Glutamic Acid-Proline-Threonine-Isoleucine-Aspartic Acid-Glutamic Acid

Peptide Bond Formation
•  Practice drawing the peptide PEPTIDE using the line
structure rules you have learned:

Why L-amino acids?
Many important macromolecules and metabolites are chiral:
Proteins, DNA, sugars…
Evolutionarily speaking:
•  Once chirality is established, it is necessarily maintained
•  L-amino acids were selected as the building blocks for
proteins in the distant past and that choice has lead to the
chiral requirements of many metabolites
Is there a special requirement for L-amino acids, or is it possible
to prepare fully functioning proteins from D-amino acids?

Is Chirality Important?

Nick Vujicic
Check youtube
...

•  One of the stereoisomers is a drug, another – teratogen
•  Structures with “small” chirality mistakes are WRONG

In vivo Peptide Bond Formation
•  Ribosomal protein synthesis:
Translation proceeds N to C
Carried out by massive ribosome complexes
•  Non-ribosomal protein/peptide synthesis (e
...
antibiotics)
Forms complex structures incorporating standard
and modified amino acids (including D-amino acids),
cyclic products, etc
Utilizes modular enzyme architecture

Levels of Protein Structure

Levels of Protein Structure
Primary Structure:
•  Linear sequence of amino acids linked by peptide bonds
Secondary Structure:
•  Defined by local interactions of the primary sequence
α-helices, β-sheets, loops & turns
Tertiary Structure:
•  Protein domains - defined by long range interactions
between secondary structural units
Quaternary Structure:
•  Associations between protein domains

Central Dogma of Molecular Biology

•  Protein primary sequence is determined by DNA and
encodes all required information for protein to fold
properly and function
•  As always in biology, there are some exceptions

A
...
sequence = primary
structure
•  Sequence of amino acids from N- to Cterminus
•  May include disulfide bonds
•  Defining polypeptides:
Oligopeptide: a few amino acids linked
Polypeptide: many amino acids linked
Protein is a large polypeptide, typically with a
MW > 10,000 Da (g/mole) cutoff
•  In reality, these terms are amorphous (“ish”)

Thought Questions:
Peptide Characteristics
•  Why is a peptide bond planar? Draw the relevant structures
to demonstrate
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Draw a trans peptide bond
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Practice by drawing peptide sequences;
think about how the side chain ionization would change
under different pH conditions based on pKa values
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