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Pictures
of the Day 2-27-08
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Amide
Structure |
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The
Unique Structure of Amide Bonds
Amides have structural characteristics that are unique among carboxylic acid
derivatives. Had you been asked in Chapter 1 to describe the geometry of an amide
bond, you probably would have predicted bond angles of 120° about the carbonyl
carbon and 109.5° about a tetrahedral amide nitrogen. In the late 1930s,
one of Linus Pauling’s most important discoveries was that the geometry
of the nitrogen atom of an amide bond in proteins is actually trigonal planar
(sp2), not tetrahedral (sp3). A large number of subsequent experiments have verified
that amides should be thought of as being best represented as the resonance hybrid
of three resonance contributing structures, not two like other carbonyl species.
In the unique third contributing structure of an amide, the lone pair on nitrogen
donates electron density to create a pi bond between carbon and nitrogen. |
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Inclusion
of the third resonance contributing structure explains why the amide nitrogen
is sp2 hybridized and therefore trigonal planar. Also, the presence of a partial
double bond (pi bond) in the resonance hybrid indicates the presence of a restricted
bond rotation about the C-N bond. In fact, the measured C-N bond rotation barrier
is on the order of 63-84 kJ (15-20 kcal)/mol in amides, enough so that the
bond does not rotate appreciably at room temperature. In addition, because
the lone pair on nitrogen is delocalized into the pi bond, it is not as available
for interacting with Lewis acids such as protons. Thus, amide nitrogens are
not basic. In fact, in acid solution, amides are protonated on the carbonyl
oxygen atom, not the nitrogen. Finally, the nitrogen lone pair electron delocalization
also reduces the electrophilic character (partial positive charge) on the carbonyl
carbon atom, reducing amide susceptibility to nucleophilic attack. |
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The
amide -NH group is a good hydrogen bond donor, while the amide carbonyl is
a good hydrogen bond acceptor, allowing primary and secondary amides to form
strong hydrogen bonds. |
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Amide
Bonds and Protein Folding
Proteins are made from amino acids connected through mostly secondary amide bonds,
which adopt the more stable trans (E) configuration. This is thought to be due
to repulsive steric interactions between side chains in the cis (Z) form that
are not present in the trans (E) form, along with more favorable dipole-dipole
interactions in the trans (E) form. Proline, the only amino acid to contain a
secondary amine, produces tertiary amide bonds in proteins, so the cis and trans forms
are of similar energy. In fact, proline cis-trans isomerism is now known to contribute
substantially to the structure and function of certain proteins. |
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Because
amide bonds are resistant to nucleophilic attack, the protein backbone is chemically
very stable near physiological pH. Proteins are, however, susceptible to cleavage
by certain specially adapted enzymes called proteases that can cleave amide
bonds under mild conditions. Some proteases are the therapeutic targets of
several recently introduced drugs.
Because of the large rotation barrier of the amide C-N bond, one out of every
three bonds in a protein backbone does not rotate, significantly reducing the
flexibility of the entire chain. In the context of protein folding, this conformational
restriction is essential, because it requires much less stabilization energy
to stably fold a chain with conformational restriction every third bond compared
to a chain with no bond restrictions. The large number of hydrogen bonds possible
along a protein backbone provide directional, non-covalent interactions that
work in concert with other non-covalent interactions to stabilize a folded structure. |
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The
folded three-dimensional structures of proteins endow them with the organization
they need to carry out a remarkable array of catalytic activities that are
the essence of the chemistry that keeps cells alive. The two basic patterns
of protein folding are the alpha helix and beta sheet. A representative protein
alpha helix and beta sheet are shown in the Figure with the trans amide bonds
highlighted in magenta and backbone hydrogen bonds shown as green broken lines.
The same backbone is shown above each structure for comparison, with side chains
removed for clarity. The prominence of amide bonds in the protein backbone
is apparent. These secondary structures are thus stabilized to a significant
extent by the hydrogen bonding and conformational restriction of the protein
backbone imposed by the amides. |
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In the above figure are representative protein alpha helix (left) and beta
strand (right). The four principle atoms of the backbone amide bonds are
highlighted in magenta and backbone hydrogen bonds are shown as broken green
lines. The upper structures are the backbone only, with side chain atoms
removed for clarity.
A representative complete protein structures in Figure Y illustrates just a
small sample of the remarkably complex and often quite beautiful folding
patterns found in proteins. Here the protein is shown in both a spacefilling
and ribbon cartoon model with coils representing alpha helices and the arrows
representing strands of a beta sheet. Scientists often use visual aids such
as these ribbon cartoons to help them visualize complex structures. Proetin
structures such as these would not be stable if it were not for the hydrogen
bonding and conformational restriction imparted by amide bonds of the protein
backbone. It is reasonable to say that the unique structural characteristics
of amide bonds have played a relatively large part in shaping the evolution
of life on our planet!
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