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Amino Acids and Peptides
Andy Howard
Introductory Biochemistry
Fall 2010, IIT
Acids, bases, amino acids
We begin looking at specific categories
of small molecules by examining acidbase equilibrium, both in general and in
amino acids
 These simple molecules are inherently
important, and they help illustrate some
general principles

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Plans






Review

Acid-base
equilibrium

Amino acid
structures

Chirality
Acid/base chemistry
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Side-chain reactivity
Peptides and
proteins
Side-chain reactivity
in context
Disulfides
Biochemistry: Amino Acids
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Review questions

1. The correct form of the free energy
equation is generally given as:
– (a) DH = DG - TDS
– (b) PV = nRT
– (c) DG = DH - TDS
– (d) DS = DH - DG
– (e) none of the above

(20 seconds for this one)
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Review questions, problem 2

2. Suppose a reaction is at equilibrium
with DH = -6 kJ mol-1 and
DS = -0.02 kJ mol-1K-1.
Calculate the temperature.
–
–
–
–
–

(a) 250K
(b) 280K
(c) 300K
(d) 310K
(e) 340K
45 seconds for this one
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Review questions, problem 3

3. Suppose the reaction AB is endergonic
with DGo = 37 kJ/mol. What would be a
suitable exergonic reaction to couple this
reaction to in order to drive it to the right?
–
–
–
–

(a) hydrolysis of ATP to AMP + PPi
(b) hydrolysis of glucose-1-phosphate
(c) hydrolysis of pyrophosphate
(d) none of the above
30 seconds for this one
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Acid-Base Equilibrium

In aqueous solution, the concentration of
hydronium and hydroxide ions is nonzero
 Define:
– pH  -log10[H+]
– pOH  -log10[OH-]
Product [H+][OH-] = 10-14 M2 (+/-)
 So pH + pOH = 14
 Neutral pH: [H+] = [OH-] = 10-7M:
pH = pOH = 7.

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So what’s the equilibrium
constant for this reaction?
Note that the equation is
H2O  H+ + OH Therefore keq = [H+][OH-] / [H2O]
 But we just said that
[H+] = [OH-] = 10-7M
 We also know that [H2O] = 55.5M
(= (1000 g / L )/(18 g/mole))
 So keq = (10-7M)2/55.5M = 1.8 * 10-16M

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Alternative approach
Assume the protonated species is H3O+
rather than H+
 Then the reaction is
2 H2O  H3O+ + OH keq = [H3O+][OH-] / ([H2O]2)
 At pH=7, [H3O+] = [OH-] = 10-7M
 Dilute solution: [H2O] = 55.5M, so
keq = 10-14 M2/ [(55.5)2 M2] = 3.24*10-18

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Henderson-Hasselbalch
Equation
If ionizable solutes are present, their
ionization will depend on pH
 Assume a weak acid HA  H+ + Asuch that the ionization equilibrium
constant is Ka = [A-][H+] / [HA]
 Define pKa  -log10Ka
 Then pH = pKa + log10([A-]/[HA])

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The Derivation is Trivial!
Ho hum:
 pKa = -log([A-][H+]/[HA])
= -log([A-]/[HA]) - log([H+])
= -log([A-]/[HA]) + pH
 Therefore pH = pKa + log([A-]/[HA])
 Often written
pH = pKa + log([base]/[acid])

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How do we use this?
Often we’re interested in calculating
[base]/[acid] for a dilute solute
 Clearly if we can calculate log([base]/[acid]) =
pH - pKa
then you can determine
[base]/[acid] = 10(pH - pKa)
 A lot of amino acid properties are expressed
in these terms
 It’s relevant to other biological acids and
bases too, like lactate and oleate

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Reading recommendations
If the material on ionization of weak
acids isn’t pure review for you, I strongly
encourage you to read the relevant
sections in Garrett & Grisham
 We won’t go over this material in detail
in class because it should be review, but
you do need to know it!

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So: let’s look at amino acids
The building blocks of
proteins are of the form
H3N+-CHR-COO-;
these are -amino acids.
 But there are others,
e.g. beta-alanine:
H3N+-CH2-CH2-COO
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These are zwitterions

Over a broad range of pH:
– the amino end is protonated and is therefore
positively charged
– the carboxyl end is not protonated and is
therefore negatively charged

Therefore both ends are charged
 Free -amino acids are therefore highly
soluble, even if the side chain is apolar
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At low and high pH:

At low pH, the carboxyl
end is protonated
At high pH, the amino
end is deprotonated
 These are molecules
with net charges

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Identities of the R groups




Nineteen of the twenty ribosomally
encoded amino acids fit this form
The only variation is in the identity of
the R group (the side chain extending
off the alpha carbon)
Complexity ranging from glycine
(R=H) to tryptophan (R=-CH2-indole)
Note that we sometimes care about
-amino acids that aren’t ribosomal—
like ornithine
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ornithine
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Let’s learn the ribosomal
amino acids.
We’ll walk through the list of 20, one or
two at a time
 We’ll begin with proline because it’s
weird
 Then we’ll go through them sequentially
 You do need to memorize these, both
actively and passively

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But first: a reminder
We often characterize a carbon atom by
specifying how many hydrogens are
attached to it
 –CH3 is methyl
 –CH2– is methylene
 –CH– is methine
|

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Special case: proline
Proline isn’t an amino
acid: it’s an imino acid
 Hindered rotation
around bond between
amine N and alpha
carbon is important to its
properties
 Tends to abolish helicity
because of that
hindered rotation

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The simplest amino acids

Glycine
H
H
O
C
C
N+
H
H

Alanine H
O-
H
H
H
methyl
C
H
H
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O
C
N+
H
These are
moderately
nonpolar
C
H
O-
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Branched-chain aliphatic aas

Valine
H
H
H
C
H
H
O
C
N+
H

C
H
H
H
H
H
O
C
N+
H
H
C
H
C
C
H
H
C
C
H
C
H
H
H
H
C
H
H
C
H
H H
H
O-
Isoleucine
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Leucine
H
H

isopropyl
C
C
H
Seriously
nonpolar
H
H
C
H
N+
H
H
H
O
C
C
H
O-
O-
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Hydroxylated, polar amino acids


Serine
Threonine
H
H
H
hydroxyl
C
H
H
H
O
C
H
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H
N+
H
C
H
O-
Biochemistry: Amino Acids
H
H
O
C
O
C
N+
H
C
H
H
O
C
H
O-
p. 23 of 74
Amino acids with carboxylate
side chains


Aspartate
Glutamate
O-
O-
C
O
carboxylate
H
H
H
methylene
C
H
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C
H
H
Biochemistry: Amino Acids
H
C
O
C
N+
H
O-
H
H
O
C
N+
H
H
C
C
H
O
C
H
O-
p. 24 of 74
Amino Acids with amide side
chains


asparagine
glutamine
H
O
N
H
H
amide
C
O
N
H
H
Note: these are
uncharged! Don’t
fall into the trap!
C
H
H
C
H
N+
H
H
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C
H
C
H
H
Biochemistry: Amino Acids
H
O
C
N+
H
O-
H
C
O
C
H
C
H
O-
p. 25 of 74
Sulfur-containing amino acids

H
Cysteine

Methionine
H
C
H
H
sulfhydryl
S
S
H
H
H
C
H
N+
H
O
C
H
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Two differences:
(1) extra methylene
(2) methylated S
H
C
H
H
C
H
O
C
C
N+
H
H
O-
H
Biochemistry: Amino Acids
C
H
O-
p. 26 of 74
Positively charged side chains
H
H
H
Guanidinium
N+
H
H
H

H
N+
C
H
H
N
C
Lysine
H
H

C
C
H
H
C
H
H
Arginine H
H
H
H
N
C
H
H
H
C
C
H
H
O
C
H
C
N+
H
H
H
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C
N+
H
O
C
H
O-
O-
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Aromatic Amino Acids


Phenylalanine
H
Tyrosine
O
H
C
C
H
phenyl
H
H
H
H
C
C
C
C
C
C
C
C
H
H
C
C
H
H
H
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C
H
H
H
O
C
N+
H
C
N+
H
H
O
C
H
C
C
H
H
O-
H
Biochemistry: Amino Acids
O-
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Histidine: a special case

Histidine
imidazole
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Tryptophan: the biggest of all

Tryptophan
indole
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Chirality
Remember:
any carbon with four non-identical
substituents will be chiral
 Every amino acid except glycine is
chiral at its alpha carbon
 Two amino acids (ile and thr) have a
second chiral carbon: C

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Ribosomally encoded amino
acids are L-amino acids

All have the same handedness at the alpha
carbon
 The opposite handedness gives you a Damino acid
– There are D-amino acids in many organisms
– Bacteria incorporate them into structures of their
cell walls
– Makes those structures resistant to standard
proteolytic enzymes, which only attack amino
acids with L specificity
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The CORN mnemonic
for L-amino acids
Imagine you’re
looking from the
alpha hydrogen
to the alpha
carbon
 The substituents
are, clockwise:
C=O, R, N:

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Abbreviations for the amino
acids

3-letter and one-letter codes exist
– All the 3-letter codes are logical
– Most of the 1-letter codes are too

6 unused letters, obviously
– U used for selenocysteine
– O used for pyrrollysine
H
– B,J,Z are used for ambiguous cases: H
B is asp/asn, J is ile/leu, Z is glu/gln
H
– X for “totally unknown”

H
Se
H
H
C
O
C
C
N+
H
O-
http://www.chem.qmul.ac.uk/iupac/AminoAcid/A2021.html
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Acid-base properties
-amino acids take part in a variety of
chemical reactivities, but the one we’ll
start with is acid-base reactivity
 The main-chain carboxylate and amine
groups can undergo changes in
protonation
 Some side chains can as well

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Letters A-F: acid-base properties
Amino
Acid
Sidechain
CH3
3-lett
abbr.
ala
1- pKa,
let COOA 2.4
*
asx
B
cysteine
CH2SH
cys
C
1.9
10.7
aspartate
CH2COO- asp
D
2.0
9.9
glutamate
(CH2)2COO-
E
2.1
9.5
phenylalanine
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CH2-phe phe
F
2.2
9.3
alanine
glu
Biochemistry: Amino Acids
pKa,
NH3+
9.9
p. 36 of 74
Letters G-L
Amino
Acid
Sidechain
H
3-lett
abbr.
gly
1- pKa,
let COOG 2.4
pKa,
NH3+
9.8
histidine
-CH2imidazole
his
H
1.8
9.3
isoleucine
CH(Me)Et ile
I
2.3
9.8
Ile/leu
*
lex?
J
2.3
9.7-9.8
lysine
(CH2)4NH3+
lys
K
2.2
9.1
leucine
CH2CHMe2
leu
L
2.3
9.7
glycine
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Letters M-S
methionine
(CH2)2-S-Me
met
M 2.1
9.3
asparagine
CH2-CONH2
asn
N 2.1
8.7
pyrrollysine
proline
see above
pyl
O 2.2
9.1
(CH2)3CH (cyc)
pro
P 2.0
10.6
glutamine
(CH2)2CONH2
gln
Q 2.2
9.1
arginine
(CH2)3guanidinium
arg
R 1.8
9.0
serine
CH2OH
ser
S 2.2
9.2
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Letters T-Z
threonine
CH(Me)OH
thr
T
2.1
9.1
selenocysteine
CH2SeH
Sec
U
1.9
10.7
valine
CH(Me)2
val
V
2.3
9.7
tryptophan
CH2-indole
trp
W
2.5
9.4
Xaa
X
2.2
9.2
unknown
tyrosine
CH2-Phe-OH
tyr
Y
glu/gln
(CH2)2-COX
glx
Z
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Remembering the abbreviations









A, C, G, H, I, L, M, P, S, T, V easy
F: phenylalanine sounds like an F
R: talk like a pirate
D,E similar and they’re adjacent
N: contains a nitrogen
W: say tryptophan with a lisp
Y: second letter is a Y
Q: almost follows N, and gln is like asn
You’re on your own for K,O,J,B,Z,U,X
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Do you need to memorize these
structures?
Yes, for the 20 major ones
(not B, J, O, U, X, Z)
 The only other complex structures I’ll
ask you to memorize are:

–
–
–
–
DNA, RNA bases
Ribose, glucose, glyceraldehyde
Cholesterol, stearate, palmitate
A few others I won’t enumerate right now.
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How hard is it to
memorize the structures?
Very easy: G, A, S, C, V
 Relatively easy: F, Y, D, E, N, Q
 Harder: I, K, L, M, P, T
 Hardest: H, R, W
 Again, I’m not asking you to memorize
the one-letter codes, but they do make
life a lot easier.

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Another review question
What amino acids are in ELVIS?
 (a) asp - lys - val - ile - ser
 (b) asn - lys - val - ile - ser
 (c) glu - leu - val - ile - ser
 (d) glu - lys - val - ile - ser
 (e) Thank you very much.
(25 seconds)
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… and another

How many of the twenty plentiful,
ribosomally encoded amino acids have
exactly one chiral center?
– (a) zero
– (b) one
– (c) seventeen
– (d) eighteen
– (e) twenty
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Main-chain acid-base chemistry





Deprotonating the amine group:
H3N+-CHR-COO- + OH- 
H2N-CHR-COO- + H2O
Protonating the carboxylate:
H3N+-CHR-COO- + H+ 
H3N+-CHR-COOH
Equilibrium far to the left at neutral pH
First equation has Ka=1 around pH 9
Second equation has Ka=1 around pH 2
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Why does pKa depend on the
side chain?

Opportunities for hydrogen bonding or
other ionic interactions stabilize some
charges more than others
 More variability in the amino terminus,
i.e. the pKa of the carboxylate group
doesn’t depend as much on R as the
pKa of the amine group
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When do these pKa values
apply?

The values given in the table are for the free
amino acids
 The main-chain pKa values aren’t relevant for
internal amino acids in proteins
 The side-chain pKa values vary a lot
depending on molecular environment:
a 9.4 here doesn’t mean a 9.4 in a protein!
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How do we relate pKa to
percentage ionization?
Derivable from Henderson-Hasselbalch
equation
 If pH = pKa, half-ionized
 One unit below:

– 90% at more positive charge state,
– 10% at less + charge state

One unit above: 9% / 91%
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Don’t fall into the trap!

Ionization of leucine:
pH
%+ve
2.3 3.3
50 10
8.7
0
9.7
0
10.7
0
% neutral 10
50
90
90
50
10
%-ve
0
0
0
10
50
90
Main
species
NH3+CHRCOOH
NH3+
CHRCOO-
NH3+
CHRCOO-
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1.3
90
Biochemistry: Amino Acids
NH2CHRCOO-
p. 49 of 74
Side-chain reactivity

Not all the chemical reactivity of amino acids
involves the main-chain amino and carboxyl
groups
 Side chains can participate in reactions:
– Acid-base reactions
– Other reactions

In proteins and peptides,
the side-chain reactivity is more important
because the main chain is locked up!
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Acid-base reactivity
on side chains

Asp, glu: side-chain COO-:
– Asp sidechain pKa = 3.9
– Glu sidechain pKa = 4.1
– That means that at pH = 5.1, a glutamate
will be ~90.9% charged

Lys, arg: side-chain nitrogen:
– Lys sidechain –NH3+ pKa = 10.5
– Arg sidechain =NH2+ pKa = 12.5
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Acid-base reactivity in histidine

It’s easy to protonate and deprotonate
the imidazole group
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Cysteine: a special case
The sulfur is surprisingly ionizable
 Within proteins it often remains
unionized even
at higher pH
H

H+
S-
S
H
H
H+
C
pKa = 8.4
H
H
O
C
C
N+
H
H
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C
O
C
C
N+
H
H
H
H
H
O-
H
Biochemistry: Amino Acids
O-
p. 53 of 74
Ionizing hydroxyls
X–O–H  X–O- + H+
 Tyrosine is easy, ser and thr hard:
– Tyr pKa = 10.5
– Ser, Thr pKa = ~13
 Difference due to resonance
stabilization of phenolate ion:

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Resonance-stabilized ion
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Other side-chain reactions
Little activity in hydrophobic amino acids
other than van der Waals
 Sulfurs (especially in cysteines) can be
oxidized to sulfates, sulfites, …
 Nitrogens in his can covalently bond to
various ligands
 Hydroxyls can form ethers, esters
 Salt bridges (e.g. lys - asp)

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Phosphorylation





ATP donates terminal phosphate to sidechain hydroxyl of ser, thr, tyr
ATP + Ser-OH  ADP + Ser-O-(P)
Often involved in activating or inactivating
enzymes
Under careful control of enzymes called
kinases and phosphatases
This is an instance of post-translational
modification
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Amino acid frequencies and
importance in active sites
Polar amino acids, particularly S, H, D,
E, K, are at the heart of most active
sites of enzymes and other globular
proteins
 Yet they’re relatively uncommon overall
in proteins
 Nonpolar amino acids (V, L, I, A) occur
with higher frequencies overall

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Peptides and proteins
Peptides are oligomers of amino acids
 Proteins are polymers
 Dividing line is a little vague:
~ 50-80 aa.
 All are created, both formally and in
practice, by stepwise polymerization
 Water eliminated at each step

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Biochemistry: Amino Acids
p. 59 of 74
Growth of oligo- or polypeptide
R1
H
H
O
C
C
N+
H
+
O-
O
C
C
N+
H
H
H
H
R2
H
O-
R1
O
H
C
O
C
H
H
N
H
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H
C
N+
H
H2O
C
R2
O-
Biochemistry: Amino Acids
p. 60 of 74
The peptide bond
The amide bond between two
successive amino acids is known
as a peptide bond
 The C-N bond between the first
amino acid’s carbonyl carbon and
the second amino acid’s amine
nitrogen has some double bond
character

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Biochemistry: Amino Acids
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Double-bond character of
peptide
H
N
C
N+
H
O
H
R1
H
C
C
C
O
R2
H
H
H
R1
H
C
N+
N+
H
O
H
C
C
C
O-
R2
H
H
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Biochemistry: Amino Acids
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The result: planarity!

This partial double bond character means the
nitrogen is sp2 hybridized
 Six atoms must lie in a single plane:
–
–
–
–
–
–
First amino acid’s alpha carbon
Carbonyl carbon
Carbonyl oxygen
Second amino acid’s amide nitrogen
Amide hydrogen
Second amino acid’s alpha carbon
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Biochemistry: Amino Acids
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Rotations and flexibility
Planarity implies  = 180º, where  is
the torsion angle about N-C bond
 Free rotations are possible about N-C
and C-C bonds

– Define  = torsional rotation about N-C
– Define  = torsional rotation about C-C

We can characterize main-chain
conformations according to , 
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Biochemistry: Amino Acids
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Ramachandran angles
G.N. Ramachandran
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Biochemistry: Amino Acids
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Preferred Values of  and 
Steric hindrance makes some values
unlikely
 Specific values are characteristic of
particular types of secondary
structure
 Most structures with forbidden values
of  and  turn out to be errors

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How far from 180º can  vary?
Remember what we said about the
partial double bond character of the C-N
main-chain bond
 That imposes planarity
 In practice it rarely varies by more than
a few degrees from 180º.

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Biochemistry: Amino Acids
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Ramachandran plot

Cf. figures in text
 If you submit a
structure to the
PDB with
Ramachandran
angles far from
the yellow
regions, be
prepared to justify
them!
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Biochemistry: Amino Acids
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How are oligo- and polypeptides
synthesized?
Formation of the peptide linkages
occurs in the ribosome under careful
enzymatic control
 Polymerization is endergonic and
requires energy in the form of GTP (like
ATP, only with guanosine):
 GTP + n-length-peptide + amino acid 
GDP + Pi + (n+1)-length peptide

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Biochemistry: Amino Acids
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What happens at the ends?
Usually there’s a free amino end and a
free carboxyl end:
 H3N+-CHR-CO-(peptide)n-NH-COO Cyclic peptides do occur
 Cyclization doesn’t happen at the
ribosome: it involves a separate,
enzymatic step.

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Reactivity in peptides & proteins

Main-chain acid-base reactivity
unavailable except on the ends
 Side-chain reactivity available but with
slightly modified pKas.
 Terminal main-chain pKavalues modified
too
 Environment of protein side chain is often
hydrophobic, unlike free amino acid side
chain
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Another iClicker question
What’s the net charge on ELVIS at
pH 7?
 (a) 0
 (b) +1
 (c) -1
 (d) +2
 (e) -2
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Biochemistry: Amino Acids
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Disulfides
In oxidizing
environments, two
neighboring
cysteine residues
can react with an
oxidizing agent to
form a covalent
bond between the
side chains
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H
H
S
S
H
H
C
H
+
H
C
(1/2)O 2
H2O
H
H
C
C
S
H
Biochemistry: Amino Acids
S
H
p. 73 of 74
What could this do?
Can bring portions of a protein
that are distant in amino acid
sequence into close proximity
with one another
 This can influence protein stability

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