10/26/2021

Chem413
Biochemistry
Part 3: Amino Acids and
Protein Structure (1/5)

1. Introduction
 The molecular building blocks of life. There
are 68 molecules that contribute to the
synthesis and primary structures of the 4
fundamental macromolecular components
of all cells: nucleic acids, proteins, glycans
and lipids.
 DNA and RNA are produced from the 8 nucleosides.
Although deoxyribose (d) and ribose (r) are saccharides,
they are an integral part of the energetically charged
nucleoside building blocks that are used to synthesize
DNA and RNA.
 There are 20 natural amino acids used in the synthesis From: Marth, J.D., 2008. A
of proteins. unified vision of the building
 Glycans derive initially from 32, and possibly more, blocks of life. Nature Cell
Biology, 10(9), p.1015.
saccharides used in the enzymatic process of
glycosylation and are often attached to proteins and
lipids, although some exist as independent
macromolecules.
 Lipids are represented by 8 recently
classified categories and contain a
large repertoire of hydrophobic and
amphipathic molecules. The number
of molecular building blocks does not
directly infer the relative structural
complexity of the repertoire of each
component. Not shown are the many
different post-synthetic modifications
of the molecules 2

1
 10/26/2021

1. Introduction

 The central dogma of molecular biology:

1. Introduction
 Proteins are one of the main building blocks of life and perform a multitude of
functions.

2
 10/26/2021

1. Introduction
 Proteins are linear biological copolymers of -amino acids (AAs) linked
through amide bonds between the carboxylic acids of one AA with the
-amino group of a second AA.

H NH2
R = sidechain
R CO2H

- Amino Acid

R1 R1
+ R2 - H2O H
N CO2
H3N CO2 H3N
H3N CO2 C-terminus
O R2
N-terminus

O R2 O R4 O R6 O
H H H H
N N N N
N N N N
H H H H
R1 O R3 O R5 O R7

1. Introduction
 Twenty amino acids are commonly found in proteins.

 These amino acids contain a variety of different functional groups:

• Alcohols (R= -OH)
• Phenols (R= -Ph-OH)
• Carboxylic acids (R= -COOH)
• Thiols (R= -SH)
• Amines (R= -NH2)
• and others.

3
 10/26/2021

1. Introduction

 Protein function depends on both

• amino acid content, and
• amino acid sequence.

 Protein fold into diverse shapes such as

• spherical
• elipsoidal
• long strands, and so on.

 All information for 3-D structure is contained in the linear sequence of

amino acids.

 To understand protein function, we must first understand the nature of

amino acids.

2. Amino Acids
 While their name implies that amino acids are compounds that contain
an —NH2 group and a —CO2H group, these groups are actually present as
—NH3+ and —CO2–, respectively, at physiological pH.

 Amino acids (AAs) exist in aqueous solution primarily at physiological pH

in the form of a dipolar ion, or zwitterion (from the German zwitter,
meaning “hybrid”).

4
 10/26/2021

2. Amino Acids
 AAs are classified as , , , etc. amino acids according the carbon that
bears the nitrogen. Only -amino acids are genetically encoded to be
monomers of proteins.
 There are 20 genetically encoded -amino acids found in peptides and
proteins.
 Among these 19 are primary amines, 1 (i.e. proline) is a secondary
amine.

H H H H H H
H2N C CO2H H2N C C CO2H H2N C C C CO2H
H H H H H H

-amino acid -amino acid -amino acid

(2-amino carboxylic acid) (3-amino carboxylic acid) (4-amino carboxylic acid)

2. Amino Acids
 In addition to the 20 amino acids commonly found in proteins, 2 others—
selenocysteine and pyrrolysine—are found in some organisms, and more
than 700 nonprotein amino acids are also found in nature. For instance:
• -Aminobutyric acid (GABA):A neurotransmitter in brain;
• Homocysteine: Found in blood and is linked to coronary heart disease
• Thyroxine: Found in the thyroid gland and acts as a hormone.

10

5
 10/26/2021

2.1. Stereochemistry of Amino Acids

 Of the 20 genetically encoded -AAs 19 are “chiral”, 1 (glycine) is achiral.
 As with carbohydrates, it is traditional to use the D and L nomenclature
with amino acids – based on the configuration of glyceraldehyde
 Naturally occurring amino acids generally have the same configuration as
L-glyceraldehyde (S-configuration at the -carbon). D-Amino acids are
found in the cell walls of bacteria. The D-amino acids are not genetically
encoded, but derived from the epimerization of L-isomers
CHO CHO CO2H CO2H
H OH HO H H2N H H2N H
CH2OH CH2OH CH3 R
D-glyceraldehyde L-glyceraldehyde L-alanine

CHO CHO CO2H CO2H

HO H H OH H2N H H2N H
H OH HO H H OH H3C H
CH2OH CH2OH CH3 CH2CH3
D-erythrose L-erythrose L-theronine L-isoleucine
(2S,3R) (2S,3S)
11

2.2. Classification of Amino Acids

 Names, 3 letter, and 1 letter abbreviations for 20 -amino acids are given
below. In current usage one letter abbreviations are being preferred in
the literature.

Alanine A, Ala Leucine L, Leu

Arginine R, Arg Lysine K, Lys
Asparagine N, Asn Methionine M, Met
Aspartic acid D, Asp Phenylalanine F, Phe
Cysteine C, Cys Proline P, Pro
Glutamine Q, Gln Serine S, Ser
Glutamic Acid E, Glu Threonine T, Thr
Glycine G, Gly Tryptophan W, Trp
Histidine H, His Tyrosine Y, Tyr
Isoleucine I, Ile Valine V, Val
12

6
 10/26/2021

2.2. Classification of Amino Acids

 Amino acids are classified on the basis of the structure of the R-group
(i.e. side chain).
• Aliphatic side chains – hydrophobic
• Polar side chains – usually –OH, -NH2, and amide containing side
chains are regardewd as being hydrophilic
• Acidic – hydrophilic
• Basic – hydrophilic
• Heterocyclic/Aromatic – hydrophilic or hydrophobic

13

2.2. Classification of Amino Acids

 Amino acids are classified on the basis of the structure of the R-group
(i.e. side chain).
• Aliphatic side chains – hydrophobic

14

7
 10/26/2021

2.2. Classification of Amino Acids

 Amino acids are classified on the basis of the structure of the R-group
(i.e. side chain).
• Polar side chains – usually –OH, -NH2, and amide containing side
chains are regarded as being hydrophilic

• Sulfur containing side

chains are generally
regarded as being
hydrophobic, however.
15

2.2. Classification of Amino Acids

 Amino acids are classified on the basis of the structure of the R-group
(i.e. side chain).
• Acidic – hydrophilic

• Basic – hydrophilic

16

8

2.2. Classification of Amino Acids
 Amino acids are classified on the basis of the structure of the R-group
(i.e. side chain).
• Heterocyclic/Aromatic – hydrophilic
• Heterocyclic/Aromatic –hydrophobic
2.2. Classification of Amino Acids
 Polar (form hydrogen bonds as
proton donors or acceptors):
• Asparagine - Asn - N
• Histidine - His - H
• Serine - Ser - S
• Threonine - Thr - T
• Tyrosine - Tyr - Y
• Cysteine - Cys - C
 Amphipathic (often found at the
surface of proteins or lipid
membranes, sometimes also
classified as polar):
• Tryptophan - Trp - W
• Tyrosine - Tyr - Y
• Methionine - Met - M (may
function as a ligand to
metal ions)
10/26/2021
17
 Charged (side chains often
form salt bridges):
• Arginine - Arg - R
• Lysine - Lys - K
• Aspartic acid - Asp - D
• Glutamic acid - Glu - E
 Hydrophobic (normally buried
inside the protein core):
• Alanine - Ala - A
• Isoleucine - Ile - I
• Leucine - Leu - L
• Methionine - Met - M
• Phenylalanine - Phe - F
• Valine - Val - V
• Proline - Pro - P
• Glycine - Gly - G
18
9
 10/26/2021

2.2. Classification of Amino Acids

19

2.2. Classification of Amino Acids

 Essential Amino Acids: All 20 of the amino acids are necessary for
protein synthesis.
• Human bodies can biosynthesize only 11 of these 20 AAs.
• The other 9 must be obtained from food, thus are essential amino
acids.

20

10
 10/26/2021

2.3. Acid-Base Properties of Amino Acids

 Amino acids have both acidic and basic groups, hence exist as zwitterions
close to neutral pH. At high pH both groups are deprotonated and at low
pH both groups are protonated.

21

2.3. Acid-Base Properties of Amino Acids

22

11
 10/26/2021

2.3. Acid-Base Properties of Amino Acids

23

2.3. Acid-Base Properties of Amino Acids

24

12
 10/26/2021

2.3. Acid-Base Properties of Amino Acids

25

2.3.1. The pKa of the Carboxylic Acid Portion

 The average pKa of an -carboxyl group is 2.19, which makes them

considerably stronger acids than acetic acid (pKa 4.76).

 The greater acidity is accounted for by the electron-withdrawing (i.e.

inductive) effect of the adjacent -NH3+ group.

The ammon ium group

has an electron-w ithd raw in g
ind uctive effect
-
RCHCOOH + H2 O RCHCOO + H3 O+ pK a = 2.19
+ +
NH 3 NH 3

26

13
 10/26/2021

2.3.1. The pKa of the Carboxylic Acid Portion

 Due to the electron-withdrawing (i.e. inductive) effect of the -NH3+

group, side chain -COOH groups are also stronger acids than acetic acid.

 The effect decreases with distance from the -NH3+ group. Compare
the following:

• -COOH group of alanine (pKa 2.35)

• -COOH group of aspartic acid (pKa 3.86)
• -COOH group of glutamic acid (pKa 4.07)

pKa 2.35 pKa 3.86 pKa 4.07

27

2.3.2. The pKa of the -NH4+

 The average value of pKa for an -NH3+ group is 9.47, compared

with a value of 10.76 for 1° alkylammonium ions

- - +
RCHCOO + H2 O RCHCOO + H3 O pKa = 9.47
+
NH3 NH2

+
CH3 CHCH3 + H2 O CH3 CHCH3 + H3 O pKa = 10.60
+
NH3 NH2

28

14
 10/26/2021

2.3.3. The Basicity of Guanidine Groups

 The side chain of arginine contains a guanidine group, which

particularly basic.

: +

:
NH2 NH2 NH2
+ H2 O
:

:
RNH C RNH C RNH C
+
NH2 NH2 NH2

:
:
NH2
+
RN C + H3 O pKa = 12.48
NH2

:
29

2.3.4. The Imidazole Group of Histidine

 The imidazole group of histidine is a heterocyclic aromatic amine. Only

one of the imidazole nitrogens is basic; the other’s lone pair is part of the
aromatic system.

H H
•• +
N NH3 + N NH3 +
-
H2 O
N+ COO •• COO-
N H3O +
H
H

N ot a part of the ••
N NH3 +
aromatic sextet;
+ pK a 6.10
the p roton accep tor •• COO- + H3 O
N
H

30

15
 10/26/2021

2.3.4. The Imidazole Group of Histidine

 The imidazole group of histidine is a heterocyclic aromatic amine. Only

one of the imidazole nitrogens is basic; the other’s lone pair is part of the
aromatic system.

31

Next Lecture (Part 3 - 2/5):

• Continue with ‘’Titration of Amino Acids’’

Reading List
• Pratt: Chapter 4, p. 87-91
• Lehninger: Chapter 3, Section 3.1
• Voet: Chapter 3, p. 52-71
• Solomons: Chapter 24, p. 1045-1053

32

16