BIOC 460 Summer 2011

Introduction to Proteins;
Amino Acids, the Building Blocks
of Proteins
Reading: Berg, Tymoczko & Stryer: Chapter 2, pp. 25-34
Appendix to Chapter 2, pp. 60-61 (visualizing protein structures)

Review General Chemistry notes for acid-base concepts (it will be assumed
you understand the material).

A very useful website for studying amino acids structures and properties:
http://www.biology.arizona.edu/biochemistry/problem_sets/aa/aa.html

Key Concepts
4 levels of protein structure:
1. Primary (1)
2. Secondary (2)
3. Tertiary (3)
4. Quaternary (4)
Properties of the 20 amino acids that occur in
peptides and proteins are crucial to the structure and
function of proteins
Stereochemistry
Relative hydrophobicity or polarity
Hydrogen bonding properties
Ionization properties
Other chemical properties

Amino Acid Structures and Chemical

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BIOC 460 Summer 2011

Protein Structure -- Overview

Primary structure: linear sequence of amino acids
polymer of amino acid residues (~50-1000)
linked by peptide bonds (covalent, amide linkages)
Terminology: amino acid residue, polypeptide (chain)
Building blocks: 20 amino acids (different side chains)
Protein function depends on correct 3-D folding of
polypeptide
3-D folded structure determined by AA sequence
Most proteins functions involve binding other molecules
Shape complementarity (steric, van der Waals
interactions)
Chemical complementarity (hydrogen bond
donors/acceptors, charge complementarity, etc.)
Often the hydrophobic effect is important in binding.
Flexibility in structure (proteins are not rocks!)

Structure of lactoferrin changes when it binds iron

(common phenomenon, induced fit)
ribbon diagram, just backbone
atoms of polypeptide chain
(easier to trace chain from one end
to the other)

Space-filling structure, all

atoms of polypeptide chain

Berg et al., Fig. 2-3

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Biological Roles of Proteins (examples)

1. Catalysis (enzymes)
2. Transport (e.g., hemoglobin - O2 transport in blood;
transport of ions across cell membranes)
3. Storage (e.g., myoglobin - oxygen storage in muscle; seed
proteins - storage of nutrients)
4. Coordinated motion (e.g., in muscle, cilia, flagella)
5. Mechanical support (e.g., collagen)
6. Protection (e.g., immune system - antibodies; blood
clotting proteins)
7. Regulation and communication (e.g., hormones,
receptors, gene activation and repression, control of
enzyme activity)
8. Generation and transmission of nerve impulses
9. Toxins (bacterial, plant, snake, insect)

Levels of Protein Structure

1. Primary structure (1 structure):
Defined sequence of AAs
linked by peptide bonds (amide linkages)
2. Secondary structure (2 structure):
local, regular/recognizable conformations observed
for parts of peptide backbone of a protein
e.g, -helix, conformation, collagen helix

3. Tertiary structure (3 structure):
3-dimensional conformation of whole folded
polypeptide chain

4. Quaternary structure (4 structure):
3-dimensional relationship of different polypeptide
chains (subunits)
how the subunits fit together and their symmetry
relationships
only in proteins with more than 1 polypeptide chain

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Levels of Protein Structure

Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., Fig. 3-16

a-Amino Acids
carboxylic acids, so a", b" g", etc. designate order of
additional C atoms on carboxyl group.
a carbon = central C atom, with 4 different substituents:
1. a-carboxyl group
2. a-amino group
3. hydrogen atom
R
4. R group = side chain
(different structures for 20 different amino acids)
Stereochemistry: D vs. L
a carbon chiral (4 different substituents)
Enantiomers (non-superimposable complete mirror
images)
All AAs in naturally occurring proteins are L-isomers.

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a-Amino Acids, Stereochemistry

Berg et al.,
Fig. 3-4

UAs BMB Biology Project

website on amino acids
Are there naturally-
As you "travel" ONward, occurring D-amino
from carbonyl C toward acids?
N of amino group,
in L-amino acids
R group is on left.

a-Amino Acids, Ionization

a-carboxyl group a-amino group

Berg et al., Fig. 2-6

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a-COOH group: a weak acid

can DONATE its proton
pKa ~ 2-3
What's the conjugate base form of the carboxyl group?
Which form is charged?
Is it a positive or a negative charge?
a-NH2 group: a weak base
unshared pair of electrons on the :N
neutral amino group can ACCEPT a proton.
pKa ~9-10
What's the conjugate acid form of the amino group?
Which form is charged?
Is it a positive or a negative charge?
pKas of a-amino and a-carboxyl groups are different for
different amino acids, and also are altered if they're the
terminal groups on chain of AAs, i.e., a peptide or protein.

Amino Acid Ionization, continued

Besides the a-carboxyl and a -amino groups, 7 of the 20

AAs have ionizable side chains.

Structures and Properties of AA side chains

Biology Project website on amino acids, highly recommended
for studying:
http://www.biology.arizona.edu/biochemistry/problem_sets/aa/aa.html

Categories of AA side chains (ONE way to classify them)

Aliphatic side chains
Aromatic side chains
Hydroxyl-containing side chains
Sulfur-containing side chains
Basic side chains
Acidic side chains
Amide side chains

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Amino Acids with Aliphatic Side Chains (nonpolar)

Which of the 20 amino acids is achiral

(has no asymmetric C)?

Which aliphatic AA has 2 chiral centers?

Amino Acids with Aromatic Side Chains

Which of the aromatic side chains would be the least polar

(the most hydrophobic)?
Do any of the aromatic side chains have an ionizable group
(the ability to dissociate a proton)? Which? Approx. pKa?

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Amino Acids with Hydroxyl-Containing Side Chains

Does either of the hydroxyl-containing amino acids have

2 chiral centers? Which?

Amino Acids with Sulfur-Containing Side Chains

Which of the two S-containing side chains would be

more hydrophobic?

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Amino Acids with Basic Side Chains

(Structures are those that predominate at pH 7)

Why is the His side chain (imidazole group) called basic

if the predominant form at pH 7 is unprotonated?

Amino Acids with Acidic Side Chains and their Amides

(Structures are those that predominate at pH 7)

Are the amide side chains of glutamine and asparagine

ionizable, i.e. can they gain or lose a proton? Why or why
not?

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Proton Dissociation Reactions of Amino Acids with

Ionizable Groups in Proteins

[side chain
carboxyls]

[imidazole group]

Berg et al., Table 2-1

Proton Dissociation Reactions of Amino Acids with

Ionizable Groups in Proteins

[thiol group]

[aromatic
hydroxyl group]

[-amino group]

[guanidino
group]

Berg et al., Table 2-1

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Titration of an amino acid with a non-ionizable R group (Gly)

Nelson & Cox,

Lehninger Principles
of Biochemistry,
4th ed., Fig. 3-10

Titration of an amino acid with an ionizable R group (His)

Nelson & Cox,

Lehninger Principles
of Biochemistry,
4th ed., Fig. 3-12b

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Classification of AA side chains by chemical properties

Nonpolar but rather H2O-soluble (not hydrophobic):

Gly, Pro

Nonpolar, hydrophobic
Ala, Val, Leu, Ile, Met, Phe, (Trp), (Cys)

Polar, uncharged at pH 7:
Amide-containing:
Asn, Gln
Hydroxyl-containing:
aliphatic OH: Ser, Thr
aromatic OH: Tyr
Aromatic:
Phe, Tyr, Trp

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Classification of AA side chains by chemical properties

Charged (at pH 6-7), polar:

Acidic ():
Asp (carboxyl), Glu (carboxyl)
Basic (+):
Lys (-amino), Arg (guanidino), (His) (imidazole)
Ionizable but predominantly uncharged at pH 7:
Cys (thiol), Tyr (phenolic OH)
Sulfur-containing:
Cys (thiol), Met (thioether)

Learning Objectives
Explain the 4 levels of protein structure: primary,
secondary, tertiary, and quaternary.
Draw the structure of a typical amino acid, indicating the
following features: -carbon, -carboxyl group, -amino
group, sidechain (R group), and ionic forms that
predominate at acidic (say, pH 1), neutral (pH 7), and basic
(pH 13) pH values.
Classify each of the 20 common amino acids found in
proteins according to side chain type (aliphatic, aromatic,
sulfur-containing, aliphatic hydroxyl, basic, acidic, amide,
hydrophilic (polar), hydrophobic (nonpolar). (These
categories overlap extensively, e.g., glutamate is acidic and
its very polar.)
Learn the general structure of each of these 20 amino
acids, with its full name and 3-letter abbreviation. DO THIS
NOW DONT PUT IT OFF. You will not have to know
how many Cs are in a side chain, but you should be able
to recognize them.

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Learning Objectives, continued

Be able to write the ionization (protonation/deprotonation)
reactions for the 9 ionizable functional groups (7 side
chains plus terminal -amino and -carboxyl groups);
determine the charge of each form (conjugate acid and
conjugate base) for each group.
Be very familiar with the approximate (typical) pKa values
of theses ionizable groups (R groups, -amino,and -
carboxyl groups) in peptides and proteins (not the free
amino acid).
Note: numerical values of these "generic " pKa values for
the ionizable functional groups in peptides and proteins
will be on the cover sheet of Exam 1.
For a given ionizable group, given its pKa and pH, be able
to determine the charge on that group.

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