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An arbitrary sub-grouping of the
20 natural amino acids
Negatively-charted at pH 7
Aspartic Acid
Asp
D
Glutamic Acid
Glu
E
Polar
Aspargine
Asn
N
Nonpolar
Alanine
Ala
A
Glutamine
Gln
Q
Important for Peptide Shape
Valine
Val
V
Glycine
Gly
G
Threonine
Thr
T
Serine
Ser
S
Positively-charted at pH 7
Proline
Pro
P
Histidine
His
H
Methionine
Met
M
Leucine
Leu
L
Cysteine
Cys
C
Lysine
Lys
K
Arginine
Arg
R
Cyclic
Isoleucine
Ile
I
Phenylalanine
Phe
F
Tyrosine
Tyr
Y
Tryptophan
Trp
W
AA’s with polar or charged side chains
can function as H-bond donors or acceptors
Negatively-charted at pH 7
Aspartic Acid
Asp
D
Glutamic Acid
Glu
E
Polar
Aspargine
Asn
N
Nonpolar
Alanine
Ala
A
Glutamine
Gln
Q
Important for Peptide Shape
Valine
Val
V
Glycine
Gly
G
Threonine
Thr
T
Serine
Ser
S
Positively-charted at pH 7
Proline
Pro
P
Histidine
His
H
Methionine
Met
M
Leucine
Leu
L
Cysteine
Cys
C
Lysine
Lys
K
Arginine
Arg
R
Cyclic
Isoleucine
Ile
I
Phenylalanine
Phe
F
Tyrosine
Tyr
Y
Tryptophan
Trp
W
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All of the amino acids are special, and we will discuss
some of their unique properties later
Negatively-charted at pH 7
Aspartic Acid
Asp
D
Polar
Glutamic Acid
Glu
E
Aspargine
Asn
N
Nonpolar
Alanine
Ala
A
Glutamine
Gln
Q
Important for Peptide Shape
Valine
Val
V
Glycine
Gly
G
Threonine
Thr
T
Serine
Ser
S
Positively-charted at pH 7
Proline
Pro
P
Histidine
His
H
Methionine
Met
M
Leucine
Leu
L
Cysteine
Cys
C
Lysine
Lys
K
Arginine
Arg
R
Cyclic
Isoleucine
Ile
I
AA’s with aromatic side chains
have polar and nonpolar bits
pKa values for AA’s (with
ionizing side chains)
Phenylalanine
Phe
F
acid
Tyrosine
Tyr
Y
Tryptophan
Trp
W
conjugate base
pKa
In general, if the pKa
of an AA side chain
is two log units from
pH 7…
… it exists entirely
in one form.
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Four “special” amino acids
glycine
proline
cysteine
histidine
All amino acids are special, but these four amino acids
will help us see how side chains might affect
protein structure and function
Glycine: the smallest amino acid and the only AA
without an R group
• First amino acid
discovered (in 1820)
from gelatin.
• “R” = hydrogen
• Reduced steric
hindrance: can adopt a
wider range of peptide
conformations
compared to other
amino acids.
Glycine is loose (accommodating)
3
For 19 amino acids, the trans geometry around the
peptide bond is heavily favored
Trans
In proline, the trans
isomer is only
slightly favored
over the cis isomer.
Cis
Heavily favored
NOTE: proline also
cannot be a
hydrogen bond
donor…
Slightly favored
Proline is the contrarian (while others zig, proline zags)
Cysteine is the only amino acid that makes nonpeptidic bonds in proteins
If there are multiple cysteines in a protein
their side chains can form disulfide bonds
cysteine
cystine
Disulfide bonds constrain
protein conformation
Cysteine is in love with itself...
it’s the narcissist (generally unhealthy)
4
Your hair is made of protein that contains lots of
disulfide bonds
Chemicals (thioacetic acid)
can break disulfide bonds.
Other chemicals (hydrogen
peroxide) can form disulfide
bonds
Chemicals can be bad for you…
The pKa of the histidine side chain is between 6 and 7
(near physiological pH)
Histidine can act as both an acid and a base at
physiological pH (it can encompass being more than one thing
at the same time -- a true intellectual)
5
Titration of L-Histidine
pH
10
5
0
Side chains of the amino acids are often the
functional components of proteins
chymotrypsin
acrosin
Factor X
Uncatalyzed rate 7-400 years
Enzymes make the rate of reactions go faster
6
Amino acids cooperate in catalysis
Asp 102
Ser 195
His 57
chymotrypsin
The catalytic triad: serine, histidine, and aspartic acid
work together to cleave amide bonds
Protein structure and folding
HUMPTY DUMPTY SAT ON A WALL. HUMPTY DUMPTY HAD A GREAT FALL.
ALL THE KING’S HORSES AND ALL THE KING’S MEN, COULDN’T PUT HUMPTY
TOGETHER AGAIN.
What happens when you cook an egg?
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Polypeptides interact in precisely
defined ways to make distinct shapes
Specific order of
amino acids
Regions of secondary
structure stably interact
Local structure of
stretch of AA’s
Higher order complex
of polypeptide chains
The folded structure of a protein determines its function.
Proteins are composed of the two common
secondary structures arranged
in different ways
Cytochrome b562
Lactic acid dehydrogenase
Antibody
We would like to understand the forces that stabilize secondary
and tertiary structure (i.e. what determines a protein structure)?
8
Pauling showed that the dipoles of
acetamide and polyglycine align in crystals
(and that the peptide bond is flat)
acetamide
Pauling predicted that polypeptide chains in proteins
would form helical chains that recapitulate this hydrogen
bonding pattern… and he was right!
In -helices, adjacent N-H groups (blue)
point in the same direction…
9
C α8
C’8
8
7
C’7
C’6
C α7
-
…and because of
this arrangement of
atoms, helices have
a macrodipole
6
C α6
5
C’5
C α5
C’4
C α3
C α4
4
C’3
3
Cα
1
C’
1
2
Cα
2
C’
2
+
Side chains of AA’s (R groups)
point away from the helix
9
In -sheets, adjacent N-H groups
point in opposite directions
R
R
Cα
N
Cα
C’
N
C
O
C
N
R
R
In -sheets, there is no opportunity to form
hydrogen bonds within one strand
Why do some sequences form -helices and
others form -sheets?
Anfinsen proposed that the primary
sequence determines protein conformation
A thermodynamic hypothesis: The 3D
structure of a protein represents the most stable
folded conformation (favorable interactions are
maximized and unfavorable interactions
minimized)…
If so… you should be able to
put Humpty Dumpty back
together again.
Christian Anfinsen, Nobel
Prize in Chemistry 1972
Egg test: Will a denatured protein
(ribonuclease A) refold to its native conformation?
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