The Chemical Basis of Life

CHAPTER 2
The Chemical Basis of Life
Copyright © 2016 John Wiley & Sons, Inc. All rights reserved.

2.0 | The Chemical Origin of Life
Researchers have hypothesized that the earliest cells (called protocells)
were very simple, made up of just nucleic acids surrounded by a
membrane, and that these cells may have formed in warm pools of water.
In 1952, Urey and Miller simulated Earth’s early atmosphere, and after two
weeks, organic compounds that included a variety amino acids and sugars
were formed.
This supports the idea that our young planet may have been ideal for
creating the organic compounds that were eventually incorporated into
early cells.
Some laboratories are now attempting to find conditions that would allow
for the formation of protocells.

2.1 | Covalent Bonds
The properties of cells and their organelles derive directly from the
activities of the molecules of which they are composed.
Impossible to understand cellular function without a reasonable knowledge
of the structure and properties of the major types of biological molecules.
The atoms that make up a molecule are joined together by covalent bonds
in which pairs of electrons are shared between pairs of atoms.
An atom is most stable when its outermost electron shell is filled, and the
number of bonds an atom can form depends on the number of electrons
needed to fill its outer shell.

A representation of the arrangement of
electrons in a number of common atoms
The electronic structure of atoms
shows the outer shell to be filled:
All except hydrogen needs 8
electrons.
An oxygen atom can fill its outer
shell by combining with two
hydrogen atoms through 2 covalent
bonds, forming a molecule of
water.
If the bond is to be broken, the
energy required is between 80 and
100 kcal per mole (kcal/mol) of
molecules.

A representation of the arrangement of
electrons in a number of common atoms
There can be single, double and
triple covalent bonds.
When two atoms of the same
element bond, the electron pairs of
the outer shell are equally shared.
When two unlike atoms bond, the
positively charged nucleus of one
atom (more electronegative) exerts
a greater attractive force on the
outer electrons than the other.
Commonly present in biological
molecules, nitrogen and oxygen are
strongly electronegative.

Polar and Nonpolar Molecules
Water’s oxygen atom attracts electrons better than does hydrogen.
The O-H bonds are polarized, one atom with a partial negative charge
and the other atom a partial positive charge.
Molecules with an asymmetric distribution of charge are polar molecules
(contain O, N, or S).
Molecules that lack electronegative atoms and strongly polarized bonds
are nonpolar (contain C, H).
The presence of polarized bonds is importance in determining molecule
reactivity: nonpolar molecules, (waxes/fats) are relatively inert,
polar/nonpolar molecules (proteins/phospholipids) can react.

Ionization
Some atoms are so strongly electronegative that they can capture
electrons from other atoms during a chemical reaction.
When the elements sodium and chlorine are mixed, the single electron
in the outer shell of sodium migrates to the electron‐deficient chlorine
atom to formed charged ions.
The chloride ion has an extra electron, has a negative charge (Cl−) and
is termed an anion.
The sodium atom, which has lost an electron, has an extra positive
charge (Na+) and is termed a cation.

2.2 | The Human Perspective
Do Free Radicals Cause Aging?
One factor that has long been imagined to drive aging: the gradual
accumulation of damage to our body’s tissues.
Atoms or molecules that have orbitals containing a single unpaired electron
tend to be highly unstable—they are called free radicals.
Free radicals may be formed when a covalent bond is broken such that
each portion keeps one‐half of the shared electrons, or they may be formed
when an atom or molecule accepts a single electron transferred during an
oxidation–reduction reaction.
Free radicals are extremely reactive and capable of chemically altering
many types of molecules, including proteins, nucleic acids, and lipids.

In 1956, Harman proposed that aging results from tissue damage
caused by free radicals.
In 1969, McCord and Fridovich discovered superoxide dismutase
(SOD), whose function was the destruction of the superoxide radical
(O2⋅−), formed when oxygen picks up an extra electron.
Hydrogen peroxide is also a potentially reactive oxidizing agent,
normally destroyed in the cell by catalase or glutathione peroxidase.

Superoxide radicals are formed within cells during normal oxidative
metabolism.
The importance of SOD is most clearly revealed in studies of mutant
bacteria and yeast that lack the enzyme; these cells are unable to
grow in the presence of oxygen.
Similarly, mice that are lacking the mitochondrial version of the
enzyme (SOD2) are not able to survive more than a week or so
after birth.
Conversely, mice that have been genetically engineered so that
their mitochondria contain elevated levels of the H2O2‐destroying
enzyme catalase live 20 percent longer.

A related area of research concerns the study of substances called
antioxidants that are able to destroy free radicals in the test tube.
Common antioxidants found in the body include glutathione,
vitamins E and C, and beta‐carotene.
Although these substances may prove beneficial in the diet
because of their ability to destroy free radicals, studies with rats
and mice have failed to provide convincing evidence that they
retard the aging process or increase maximum life span.

2.3 | Noncovalent Bonds
Intra- and intermolecular interactions are governed by a variety of weak
linkages (about 1 to 5 kcal/mol) called noncovalent bonds.
These bonds do not depend on shared electrons but attractive forces
between atoms having an opposite charge.
Even though individual noncovalent bonds are weak, when large numbers of
them act in concert, as between the two strands of a DNA molecule or
between different parts of a large protein, their attractive forces are additive.
Taken as a whole, they provide the structure with considerable stability.

The dissolution of a salt crystal.
Ionic bonds: Attraction between charged atoms
A NaCl crystal is held together by
an electrostatic attraction between
Na+ and Cl− ions, called an ionic
bond.
Ionic bonds within a crystal may be
quite strong, yet in water, these
ions becomes surrounded by water
molecules.
This inhibits oppositely charged
ions from approaching one another
closely enough to form ionic bonds.

Ionic bonds: Attraction between charged atoms
Noncovalent ionic bonds
between DNA and protein
Weak ionic bonds between oppositely
charged groups of large biological
molecules are of considerable
importance.
Negatively charged phosphate atoms
in a DNA molecule are closely
associated with positively charged
groups on the surface of a protein
through ionic bonds.
Ionic bonds in a cell are weak (3
kcal/mol) due to water, but deep
within the core of a protein, where
water is often excluded, bonds can be
much stronger.

Hydrogen bonds
Hydrogen Bonds
Hydrogen bears a partial positive charge when
covalently bonded to an electronegative atom.
This hydrogen atom can approach a second
electronegative atom to form an interaction called a
hydrogen bond.
Hydrogen bonds (1 kcal/mol) are easily broken and
occur between most polar molecules.
Since their strength is additive, the large number of
hydrogen bonds between the strands makes the DNA
duplex a stable structure.

Hydrophobic interactions reduce
exposure to hydrophilic molecules
Hydrophobic Interaction and Van der Waals Forces
Polar molecules associate with water
and are hydrophilic.
Nonpolar molecules lack the charged
regions that would attract them to water
molecules and are hydrophobic.
They are forced into aggregates to
reduce exposure to water, called a
hydrophobic interaction.
Not true bonds because they result from
an energetic drive to exclude water
away from the hydrophobic surfaces

Van der Waals forces operate at
optimum distances and are maximized
by complementary surfaces.
Hydrophobic Interaction and Van der Waals Forces
Hydrophobic groups can form weak
bonds based on electrostatic attractions.
Covalent bonds in a nonpolar molecule
can have transient asymmetric electron
distributions to cause charge separation,
or dipoles.
Two very close molecules with transitory
dipoles can have a weak attractive force,
called a van der Waals force (0.1 to 0.3
kcal/ mol).
Biological molecules that interact with
one another often possess
complementary shapes.

The structure of water is suitable for
sustaining life: 1) It is asymmetric, both H
atoms are on one side; 2) Both covalent
O–H bonds are highly polarized; 3) All
three atoms readily form H-bonds.
Evaporation requires that water
molecules break their hydrogen bonds,
taking energy to convert water to steam.
Mammals take advantage of this when
they sweat because the heat required to
evaporate the water is absorbed from the
body, which thus becomes cooler. Hydrogen bond formation between
neighboring water molecules
The Life-Supporting Properties of Water

Hydrogen bond formation between
neighboring water molecules
The cell contains a remarkably complex
mixture of dissolved substances, or solutes.
Water is able to dissolve more types of
substances than any other solvent and
helps determines the structure of molecules
and their types of interactions.
Water is the fluid matrix around which the
insoluble fabric of the cell is constructed and
the medium through which materials move
between compartments.
It is a reactant or product in many cellular
reactions; and it protects the cell in many
ways—from excessive heat, cold, or
damaging radiation.

The importance of water in
protein structure
Water can form weak interactions with
so many different types of polar organic
molecules like amino acids and sugars.
Water helps maintaining the structure
and function of macromolecules and the
complexes that they form.
The water molecules can hydrogen
bond to each other and to specific
amino acids of a protein subunit.

Acids release protons.
Bases accept protons.
Amphoteric molecules can act as either acids or bases. For example, water:
H3O ↔ H+ + H2O ↔ OH– + H+
Acid Amphoteric Base
molecule
Acidity is measure using the pH scale.
pH = –log [H+]
The ion product constant for water is
Kw = [H+][OH–] = 10-14 at 25oC.
As [H+] increases, [OH–] decreases so that the product equals 10–14.
2.4 | Acids, Bases, and Buffers

Biological processes are sensitive to pH.
Changes in pH affect the ion state and function of proteins.
Buffers in living systems resist changes in pH.
For example, bicarbonate ions and carbonic acid buffer the blood:
HCO3
– + H+ ↔ H2CO3
Bicarbonate Hydrogen Carbonic
ion ion acid
2.4 | Acids, Bases, and Buffers

2.5 | The Nature of Biological Molecules
Compounds produced by living
organisms are called biochemicals.
Most of the dry weight of an organisms
consists of molecules containing atoms
of carbon.
The chemistry of life centers around the
chemistry of the carbon atom. Having
four outer‐shell electrons, a carbon atom
can bond with up to four other atoms.
Each carbon atom is able to bond with
other carbon atoms so as to construct
molecules with backbones containing
long chains of carbon atoms, which may
be linear, branched, or cyclic.

Cholesterol illustrates various
arrangements of carbon atoms.
The size and electronic structure of
carbon make it uniquely suited for
generating over several hundred
thousand molecules.
The simplest group of organic
molecules, the hydrocarbons, contain
only carbon and hydrogen atoms.
As more carbons are added, the
skeletons of organic molecules
increase in length and their structure
becomes more complex.
Structure of cholesterol

Functional Groups
Hydrocarbons do not occur in significant amounts within most living cells.
Many important organic molecules in biology contain chains of carbon atoms,
with certain hydrogen atoms are replaced by various functional groups.
Functional groups often behave as a unit and give organic molecules their
physical properties, chemical reactivity, and solubility in aqueous solution.
The most common linkages between functional groups are ester bonds, which
form between carboxylic acids and alcohols, and amide bonds, which form
between carboxylic acids and amines.

Monomers and polymers:
polymerization and hydrolysis.
A Classification of Biological Molecules by Function
Organic molecules found in cells can be
divided into categories based on their
role in metabolism.
Macromolecules. Huge highly organized
molecules that form the structure and
carry out the activities of cells.
Macromolecules can be divided into four
major categories: proteins, nucleic acids,
polysaccharides, and certain lipids.
The first three types are polymers
composed of a large number of low‐
molecular‐weight building blocks, or
monomers.

An overview of the types of
biological molecules that make up
various cellular structures.
The localization of these molecules can
be found in a number of cell structures.
The building blocks of macromolecules.
Most cell macromolecules are short-
lived, except DNA, and are continually
broken down and replaced.
Cells contain a supply of small
precursors ready to be added into
macromolecules.
Sugars, precursors of polysaccharides;
amino acids, precursors of proteins;
nucleotides, precursors of nucleic acids;
fatty acids, incorporated into lipids.

Metabolic intermediates (metabolites). Molecules are synthesized in a
step‐by‐step sequence in a series of chemical reactions termed a
metabolic pathway. The compounds formed along the pathways are
called metabolic intermediates.
Molecules of miscellaneous function. Include such substances as vitamins,
which function primarily as adjuncts to proteins; certain steroid or amino
acid hormones; molecules involved in energy storage, such as ATP;
regulatory molecules such as cyclic AMP; and metabolic waste products
such as urea.

2.6 | Carbohydrates
Carbohydrates (or glycans) include simple sugars (or
monosaccharides) and all larger molecules constructed of sugar
building blocks.
Carbohydrates function primarily as stores of chemical energy and
as materials for biological construction.
Most sugars have the general formula (CH2O)n.
The sugars of importance in cellular metabolism have values of n
that range from 3 to 7: three carbons (trioses), four carbons
(tetroses), five carbons (pentoses), six carbons (hexoses), and
seven carbons (heptoses).

The structures
of sugars
2.6 | Carbohydrates
The Structure of Simple Sugars
A sugar molecule has a backbone of carbon atoms linked together in a linear
array by single bonds.
Each carbon atom is linked to a single hydroxyl group, except for one that
bears a carbonyl (C O) group.
If the carbonyl group is located at an internal position the sugar is a ketose.
If the carbonyl is located at one end, the molecule is known as an aldose.

2.6 | Carbohydrates
The Structure of Simple Sugars
Sugars tend to be highly water soluble due to their hydroxyl groups.
Sugars more than 5 carbons self‐react to produce a ring‐containing molecule.
A tiny fraction of molecules in solution are linear form, but the terminal
aldehyde group can react with proteins like hemoglobin.
Production of a modified hemoglobin called Hemoglobin A1c is often used in
blood tests to track the progress of diabetes.
The structures
of sugars

Stereoisomerism of glyceraldehyde.
2.6 | Carbohydrates
Stereoisomerism
Carbon bonding groups project away from the
center of a tetrahedron into its four corners.
Glyceraldehyde, the only aldotriose, has a
carbon atom linked to four different groups.
If all groups are different then there are two
non-superimposable configurations.
Stereoisomers or enantiomers are mirror
images with the same chemical reactivities.
The molecule is called D‐glyceraldehyde if
the hydroxyl group projects to the right, and
L‐glyceraldehyde if it projects to the left.
Carbon 2 as a site of stereoisomerism is
referred to as an asymmetric carbon.

Aldotetroses.
2.6 | Carbohydrates
Stereoisomerism
As the backbone length increases, so
does the number of asymmetric carbon
atoms and stereoisomers.
Aldotetroses have two asymmetric
carbons and four different configurations.
Designation is based on the arrangement
of groups attached to the asymmetric
carbon atom farthest from the aldehyde.
If the hydroxyl group of this carbon
projects to the right, the aldose is a
D‐sugar; if it projects to the left, it is an
L‐sugar.

Formation of an a- and b-pyranose
2.6 | Carbohydrates
Stereoisomerism
The C1 of the pyranose ring has four
different groups and becomes a new
center of asymmetry within the sugar
molecule.
Because of this extra asymmetric
carbon atom, each type of pyranose
exists as α and β stereoisomers.
The molecule is an α‐pyranose when
the OH group of the first carbon
projects below the plane of the ring,
and a β‐pyranose when the hydroxyl
projects upward.

Disaccharides: Sucrose and lactose
2.6 | Carbohydrates
Linking Sugars Together
Sugars can be joined by covalent
glycosidic bonds between the
carbon atom C1 of one sugar and
the hydroxyl group of another
sugar, generating a C-O-C linkage.
Molecules composed of only two
sugar units are disaccharides and
serve primarily as readily available
energy stores.
Sucrose is a major component of
plant sap, while lactose found in
milk supplies newborn mammals
with fuel.

Polysaccharides are polymers of sugars joined by glycosidic bonds.
Glycogen is an animal product made of branched glucose polymers.
Starch is a plant product made of both branched and unbranched glucose
polymers.
Polysaccharides: identical sugar monomers but dramatically different properties
2.6 | Carbohydrates
Nutritional Polysacchararides

Cellulose, chitin, and glycosaminoglycans (GAGs): structural polysaccharides
Cellulose: plant product made of unbranched polymers
Chitin: component of invertebrate exoskeleton made
GAGs: composed of two different sugars and found in extracellular space.
Polysaccharides: identical sugar monomers but dramatically different properties
2.6 | Carbohydrates
Structural Polysacchararides

Fats and fatty acids
2.7 | Lipids
Fats
Lipids dissolve in organic solvents, not
water.
Important cellular lipids include fats,
steroids, and phospholipids.
Fats have glycerol linked by ester bonds to
three fatty acids, termed a triacylglycerol.
Fatty acids are long, unbranched
hydrocarbon chains with a single carboxyl
group at one end.
Fatty acids are amphipathic, with a
hydrophobic hydrocarbon chain is, and
hydrophilic the carboxyl group.

Soaps consist
of fatty acids
2.7 | Lipids
Fats
Soaps owe their grease‐dissolving
capability to the fact that the
hydrophobic end of each fatty acid
can embed itself in the grease,
whereas the hydrophilic end can
interact with the surrounding water.
As a result, greasy materials are
converted into complexes (micelles)
that can be dispersed by water.

2.7 | Lipids
Fats
Fatty acids differ in their length (14-20
carbons) and presence of double bonds.
Fatty acids that lack double bonds are
saturated, those with double bonds are
unsaturated.
Naturally occurring fatty acids have double
bonds in the cis configuration, which
produce kinks in a fatty acid chain.
The more double bonds, the less effective
these long chains can be packed together.
This lowers the temperature at which a
fatty acid‐containing lipid melts.

2.7 | Lipids
Fats
Fats that are liquid at room temperature
are described as oils.
Solid shortenings made from unsaturated
vegetable oils have double bonds reduced
with hydrogen through hydrogenation.
This converts some cis double bonds into
trans fats, which are straight rather than
kinked.
A molecule of fat can contain three
identical fatty acids or it can be a mixed
fat, containing more than one fatty acid.

The structure of steroids.
2.7 | Lipids
Steroids
Steroids are built around a
four‐ringed hydrocarbon skeleton.
Cholesterol is found in animal cell
membranes and is a precursor of the
steroid hormones testosterone,
progesterone, and estrogen.
Cholesterol is largely absent from
plant cells, which is why vegetable
oils are “cholesterol‐free.”

The phospholipid phosphatidylcholine.
2.7 | Lipids
Phospholipids
A phospholipid molecule resembles a
fat, but has only two fatty acid chains
not three, so it is a diacylglycerol.
The third hydroxyl of glycerol is
bonded to a phosphate group, which
is bonded to a small polar group like
choline.
Phospholipids have two ends with
different properties: one end contains
a phosphate group (hydrophilic); the
other end has two fatty acid tails
(hydrophobic).

Biological structures composed
predominantly of protein
2.8 | Building Blocks of Proteins
Proteins are macromolecules that carry
out a cell’s activities.
Enzymes accelerate reactions;
structural proteins provide mechanical
support;
hormones have a regulatory functions;
receptors determine what a cell reacts to;
contractile filaments and molecular
motors provide biological movements.
Proteins have shapes and surfaces that
allow them to interact selectively with
other molecules, so they exhibit a high
degree of specificity.

Amino acid structure. Ball-and-
stick model, chemical formula, and
peptide bond formation.
The Structure of Amino Acids
Proteins are unique polymers made of amino
acid monomers.
Twenty different amino acids, with different
chemical properties, are commonly used in
the construction of proteins.
All amino acids have a carboxyl and an
amino group, separated by a single carbon
atom, the α‐carbon.
In a neutral solution, the α‐carboxyl group
loses its proton and is negatively charged,
and the α‐amino group accepts a proton and
is positively charged.
In the cell, this reaction occurs on a ribosome
as an amino acid is transferred from a carrier
(a tRNA molecule) onto the end of the
growing polypeptide chain.

Amino acid stereoisomerism.
Amino acids have asymmetric
carbon atoms.
With the exception of glycine, the
α‐carbon of amino acids bonds to
four different groups, two
stereoisomers can exist only so
that each amino acid can exist in
either a D or an L form.
Amino acids used in the synthesis
of a protein on a ribosome are
always L‐amino acids.

During protein synthesis, an amino acid is
joined to two other amino acids, forming a
long polymer called a polypeptide chain.
Amino acids are joined by peptide bonds
from linking the carboxyl group of one
amino acid to the amino group of its
neighbor, with the elimination of water.
Once incorporated into a polypeptide
chain, amino acids are termed residues.
The N‐terminus contains an amino acid
with a free α‐amino group, and the residue
at the opposite end, the C‐terminus, has a
free α‐carboxyl group.

The Properties of the Side Chains
The backbone of the polypeptide is composed of that part of each
amino acid that is common to all of them.
The side chain or R group, bonded to the α‐carbon, is highly variable
among the 20 building blocks, which gives proteins their diverse
structures and activities.
The side chains are important in both:
intramolecular interactions, which determine the structure and
activity of the molecule, and
intermolecular interactions, which determine the relationship of a
polypeptide with other molecules, including other polypeptides.

The chemical
structures of
amino acids
R groups usually fully charged (lysine, arginine, aspartic acid, glutamic acid)
at pH 7; side chains are relatively strong organic acids & bases.
Can form ionic bonds due to charges; histones with arginine bind to the
negatively charged phosphate DNA backbone.
Histidine is usually only partially charged at pH 7; often important in enzyme
active sites due to its ability gain or lose a proton in physiologic pH ranges.

The ionization of charged,
polar amino acids.
Ionization reactions of glutamic
acid and lysine at physiologic
pH show that their side chains
are almost always present in
the fully charged state.
Consequently, they are able to
form ionic bonds with other
charged species in the cell.

The chemical
structures of
amino acids
Side chains have a partial negative or positive charge and thus can
form hydrogen bonds with other molecules including water.
These amino acids are often quite reactive.
Asparagine and glutamine are amides of aspartic and glutamic acid.

The chemical
structures of
amino acids
Side chains are hydrophobic and unable to form electrostatic bonds
or interact with water.
Side chains of this group generally lack oxygen and nitrogen.
Vary in size and shape, which allows tight packing into protein core,
associating by van der Waals forces and hydrophobic interactions.

Glycine: small R group that makes backbone flexible so it is useful in protein
hinges, and size allows 2 protein backbones to closely approach each other
Proline: R group forms ring with amino group (imino acid), and is bulky so
doesn’t fit into orderly secondary structure
Cysteine: R group has reactive -SH which forms disulfide (-S-S-) bridge with
other cysteines often at some distance away in polypeptide backbone
The chemical
structures of
amino acids

Formation of disulfide bonds:
oxidation and reduction of bonds
between two cysteine residues
Disulfide bridges often form between
two cysteines that are distant from one
another in the polypeptide backbone or
even in two separate polypeptides.
Disulfide bridges help stabilize the
shapes of proteins.
When someone gets a “perm” to make
their hair curlier, a reducing agent
breaks the disulfide bridges, letting the
keratin filaments slide past each other.
When the reducing agent is washed
out, disulfide bridges re‐form, locking
the keratin in the new positions.

Amino acids found in proteins can be altered after their
incorporation into a polypeptide chain, which are called
posttranslational modifications (PTMs).
The most widespread and important PTM is the reversible
addition of a phosphate group to a serine, threonine, or
tyrosine residue.
Lysine acetylation is another important PTM affecting
thousands of proteins in a mammalian cell.
PTMs can modify a protein’s 3D structure, level of activity,
localization within the cell, life span, and/or its interactions
with other molecules.

Hydrophobic and hydrophilic amino acid
residues in the protein cytochrome c
The ionic, polar, or nonpolar character
of side chains is very important in
protein structure and function.
Soluble proteins generally have polar
residues at their surface to interact with
water.
Non-polar residues are found in the
core tightly packed together, where
water is excluded.
Hydrophobic interactions are a driving
force during protein folding and
contribute substantially to the overall
stability of the protein.

2.9 | Primary and Secondary Structures of Proteins
Primary Structure
The intimate relationship between form and function is
best illustrated than with proteins.
Protein structure can be described at several levels of
organization, each emphasizing a different aspect and
each dependent on different types of interactions.
Four levels are described: primary, secondary, tertiary,
and quaternary.
Primary structure, concerns the amino acid sequence of
a protein, whereas the latter three levels concern the
organization of the molecule in space.

Scanning electron micrograph:
Red blood cell sickle cell anemia
Primary Structure
The primary structure of a
polypeptide is the linear sequence of
amino acids that constitute the chain.
The degree to which changes in the
primary sequence are tolerated
depends on the degree to which the
shape of the protein or the critical
functional residues are disturbed.
Sickle cell anemia results solely from
a single change (glutamic acid to
valine) in amino acid sequence within
the hemoglobin molecule.

The a-helix: structure and
physical characteristics
Secondary Structure
Secondary structure describes the
conformation of portions of the
polypeptide chain.
Depending on the amino acid sequence.
the backbone of the polypeptide can
assume the form of a cylindrical, twisting
spiral called the alpha (a) helix.
The backbone lies on the inside of the
helix and side chains project outward.
The helical structure is stabilized by
hydrogen bonds between the atoms of
one peptide bond and those situated
above and below it along the spiral.

The b-pleated sheet:
structure and physical
characteristics
Secondary Structure
The beta (b) sheet has several segments
of a polypeptide lying side by side that
form a folded or pleated conformation.
Hydrogen bonds are perpendicular to the
long axis and project across from one
part of the chain to another.
Sheets can be arranged either parallel or
antiparallel to each other.
β strands are extended and resist tensile
forces. Silk has an extensive amount of β
sheet, and is five times stronger than
steel of comparable weight.

Ribbon model of
ribonuclease
Secondary Structure
Additional secondary structures
include hinges, turns, loops, or
finger‐like extensions.
Often, these are the most flexible
portions of a polypeptide chain and
the sites of greatest biological activity.
In a ribbon model showing secondary
structure, α helices are represented
by helical ribbons, β strands as
flattened arrows, and connecting
segments as thinner strands.

An X-ray diffraction
pattern of myoglobin
2.10 | Tertiary Structure of Proteins
Tertiary structure describes the
conformation of the entire polypeptide.
Secondary structure is stabilized by
hydrogen bonds, while tertiary structure
is stabilized by noncovalent bonds
between the side chains of the protein.
Secondary structure is limited to a
small number of conformations, but
tertiary structure is virtually unlimited.
The detailed tertiary structure of a
protein is usually determined using the
technique of X‐ray crystallography.

Tertiary structure can also be determined by nuclear magnetic resonance
(NMR) spectroscopy, which uses a magnetic field to probe proteins with radio
waves to determine distances between atoms.
X‐ray crystallography provides higher resolution structures for larger proteins
but is limited by the ability to get any given protein to form pure crystals.
NMR does not require crystallization, provides information about dynamic
changes in structure, and can rapidly reveal drug binding sites, but is difficult
to use on larger proteins.
NMR spectroscopy
reveals tertiary structure
without crystallization

For many years it was presumed that all proteins had a fixed 3D structure,
which gave each protein its unique properties and specific functions; however
many proteins have regions that lack a defined shape like the PrP protein.
Disordered segments are enriched in charged/polar residues and deficient in
hydrophobic residues, and can undergo a physical transformation after
binding to an appropriate partner and assume a defined, folded structure.
Most proteins are categorized by shape as either fibrous proteins, which are
elongated, or globular proteins, which are compact.
Extracellular materials are fibrous proteins, like collagen and elastin of
connective tissues, and keratin of hair and skin, and silk. In contrast, most
proteins within the cell are globular proteins.

The three-dimensional
structure of myoglobin.
Myoglobin: The First Globular Protein Whose Tertiary Structure Was Determined
The first glimpse at the tertiary structure
of a globular protein was myoglobin.
Myoglobin functions in muscle tissue as
a storage site for oxygen, bound to an
iron atom in the center of a heme
group.
Approximately 75 percent of the 153
amino acids in the polypeptide chain
are in the α‐helical conformation, and
no β sheet was found.

Types of non-covalent
bonds maintaining the
conformation of proteins
Myoglobin: The First Globular Protein Whose Tertiary Structure Was Determined
Myoglobin contains no disulfide bonds;
the tertiary structure is held together by
noncovalent interactions.
All of the noncovalent bonds thought to
occur between side chains within
proteins—hydrogen bonds, ionic bonds,
and van der Waals forces—have been
found.
Unlike myoglobin, most globular proteins
contain both α helices and β sheets.

Tertiary Structure May Reveal Unexpected Similarities in Proteins
Different sequences,
similar structure
Similarity in primary sequence is often
used to decide whether two proteins
may have similar structure and function.
Sometimes proteins unrelated at the
primary sequence level have similar
tertiary structures.
Interactions and enzymatic activity of a
protein are deduced from the tertiary
structure.
Actin (eukaryotic) and MreB
(prokaryotic) show no similarity at the
primary level but do at the tertiary level.

Proteins are made up of
domains that can be conserved.
Protein Domains
Most eukaryotic proteins have two or
more spatially distinct modules, or
domains, that fold independently.
The different domains often represent
parts that function semi‐independently.
Protein domains are often identified with
a specific function, and the functions of
a newly identified protein can usually be
predicted by its domains.
Shuffling of domains during evolution
creates proteins with unique
combinations of activities.

Dynamic movements within the
enzyme acetylcholinesterase.
Dynamic Changes Within Proteins
Proteins are not static and inflexible, but
capable of internal movements.
The X‐ray crystallographic structure of a
protein can be considered an average
structure, or “ground state.”
NMR can monitor shifts in hydrogen bonds,
waving movements of external side chains,
and the full rotation of the aromatic rings of
tyrosine and phenylalanine residues.
Non-random movements within a protein
triggered by binding of a specific molecule
are called conformational changes.

2.11 | Quaternary Structure of Proteins
Drawing of transforming
growth factor‐β2
Most proteins have more than one
chain, or subunit, linked by covalent
disulfide bonds or held together by
noncovalent bonds.
Proteins composed of subunits are
said to have quaternary structure.
A protein composed of two identical
subunits is described as a homodimer,
whereas a protein composed of two
nonidentical subunits is a heterodimer.

Hemoglobin: a and b globin
The Structure of Hemoglobin
The best‐studied multisubunit protein is
hemoglobin, the O2‐carrying protein of red
blood cells.
Hemoglobin consists of two α‐globin and
two β‐globin polypeptides, each of which
binds a single molecule of oxygen.
Binding of oxygen causes a bound iron
atom to move closer to a heme group,
which leads to increasingly larger
movements within and between subunits.
This revealed that the complex functions
of proteins may be carried out by means
of small changes in their conformation.

Protein-Protein Interactions
Different proteins can become
physically associated to form a much
larger multiprotein complex.
Once two molecules come into close
contact, their interaction is stabilized
by noncovalent bonds.
The pyruvate dehydrogenase complex
consists of 60 polypeptide chains
constituting three different enzymes.
The product of one enzyme can be
channeled directly to the next enzyme
in the sequence without becoming
diluted in the cell.
Pyruvate dehydrogenase:
a multiprotein complex

Protein–protein interactions:
complementary molecular surfaces of
portions of two interacting proteins
Protein-Protein Interactions
The SH3 domain, found in more than
200 proteins, is involved in cell
signaling.
The surface of an SH3 domain contains
shallow hydrophobic “pockets” that
become filled by complementary
“knobs” projecting from another protein.
Structural domains act as adaptors to
mediate interactions between proteins.
Protein-protein interactions are
regulated by modifying key amino acids
with phosphate groups.

Denaturation and
refolding of ribonuclease
2.12 | Protein Folding
The unfolding of a protein is termed
denaturation, and it can be brought
about by detergents, organic solvents,
radiation, heat, and compounds such as
urea.
Ribonuclease molecules that had
re‐formed from the unfolded protein
were indistinguishable both structurally
and functionally from the correctly folded
molecules present at the beginning of
the experiment.
The linear sequence of amino acids
contained all of the information required
for the formation of the polypeptide’s 3D
conformation.

First step: Formation of secondary
structure or collapse driven by
hydrophobic interactions
Dynamics of Protein Folding
Protein folding could arise by
secondary structure formation
followed by subsequent folding
driven by hydrophobic interactions.
Alternatively, initial hydrophobic
collapse to form a compact structure
in which the backbone adopts a
native‐like shape, could be followed
by secondary structure development.
Most proteins probably fold by a
middle‐of‐the‐road scheme in which
secondary structure formation and
compaction occur simultaneously.

Along the folding pathway
Dynamics of Protein Folding
A transient structure during folding
resembles the native protein but lacks
many of the specific interactions
between amino acid side chains.
If a protein is closely related at the
primary sequence level with another
protein whose tertiary structure is
known, then one can predict the tertiary
structure of the unknown protein.
Aligning the amino acids of the unknown
protein onto the corresponding amino
acids in the protein whose structure is
known is called threading.

The role of molecular chaperones
in encouraging protein folding
The Role of Molecular Chaperones
Not all proteins can assume their final tertiary structure by self‐assembly.
Proteins undergoing folding have to be prevented from interacting non-
selectively with other molecules in the crowded compartments of the cell.
“Helper proteins”, or molecular chaperones, bind to short stretches of
hydrophobic amino acids to help unfolded proteins achieve their proper 3D
conformation.

The role of molecular chaperones
in encouraging protein folding
The Role of Molecular Chaperones
Chaperones of the Hsp70 family bind to polypeptides as they emerge from the
ribosome and prevent them from binding to other proteins in the cytosol.
Proteins can be released by the chaperones to spontaneously fold into their
native state, or repeatedly bound and released until they are fully folded.
Larger polypeptides are transferred to a different type of chaperone called a
chaperonin, a cylindrical protein complex that provides a folding environment.
TRiC is a chaperonin thought to assist in the folding of up to 15 percent of the
polypeptides synthesized in mammalian cells.

Protein Misfolding Can Have Deadly Consequences
Creutzfeld‐Jakob disease (CJD), is a rare, fatal disorder that can be
inherited or acquired that attacks the brain, causing a loss of motor
coordination and dementia.
Eating contaminated beef from cows suffering from “mad cow
disease” caused people to acquire CJD.
Islanders of Papua, New Guinea contract “kuru,” a spongiform
encephalopathy, from eating brain tissue of a recently deceased
relative.
The infectious agent responsible for CJD lacked nucleic acid and
instead was composed solely of protein, called a prion.

A contrast in structure between
normal and infectious prion protein
The prion protein is encoded by a gene
within the cell’s own chromosomes.
In normal brain tissue PrpC (prion protein
cellular) is made, while in CJD patients
PrpSc (prion protein scrapie) is present.
PrpC is soluble and is destroyed by
protein‐digesting enzymes, while PrpSc
forms insoluble fibrils and is resistant to
digestion.
Structures are different: PrpC is mainly
α‐helical and PrpSc is largely β sheet.
PrpSc can bind to PrpC) and cause it to
fold into the abnormal form.

Alzheimer’s disease (AD) is a common
disorder that strikes as many as 10
percent of individuals who are at least
65 years old.
AD patients exhibit memory loss,
confusion, and loss of reasoning ability.
The brain of a person with AD contains
fibrillar deposits of an insoluble
material referred to as amyloid.
The fibrillar deposits result from the
self‐association of a polypeptide
composed predominantly of β sheet.
Alzheimer’s disease

Formation of the Aβ peptide
The amyloid hypothesis contends
that the disease is caused by the
production of the amyloid /b-
peptide (A/b), part of the amyloid
precursor protein (APP).
Aβ is released after cleavage by
β‐secretase and γ‐secretase into
a predominant (Aβ40) or minor
(Aβ40) species.
Aβ42 tends to refold into a
conformation that contains
considerable β sheet, and can
self‐associate to form small
complexes.

Formation of the Aβ peptide
Aβ42 overproduction can be caused by
duplication of the APP gene, mutations in
the APP gene, or mutations in genes
(PSEN1/PSEN2) encoding for γ‐secretase.
Strategies of new drugs for the prevention
and/or reversal of mental decline:
(1)Prevent the initial formation of the Aβ42
peptide;
(2)Remove the Aβ42 peptide (or amyloid
deposits) once it has been formed;
(3)Prevent interaction between Aβ
molecules to eliminate formation of both
oligomers and fibrillar aggregates.

Amyloid plaque detection in normal
(top) and diseased (bottom) brains.
Although studies with animal models for
AD have shown promising results, human
clinical trials have proven less successful.
Aβ42 vaccination had had no effect on
preventing disease progression.
A “preventive trial” was begun in 2012 for
early‐onset AD patients to block the future
buildup of amyloid to prevent the disease.
Brain‐imaging procedures reveal amyloid
deposits in the brains of individuals long
before any symptoms of AD have
developed.

Some proteins can self-assemble from purified subunits.
Other proteins require molecular chaperones for proper folding.
Molecular chaperones may protect protein structure during the heat
shock response.
The heat shock response involves synthesis of heat shock proteins
that prevent denaturation of existing proteins.
2.14 | Experimental Pathways
Helping Proteins Reach Their Proper Folding State

Heat shock proteins and other chaperones prevent aggregation of
denatured or newly synthesized proteins.
Chaperones also move newly synthesized proteins across membranes.
The protein GroEL is synthesized in E. coli is essential for the proper
folding of other cellular proteins.
GroEL
models

GroEL acts in conjunction with
another protein, GroES.
Attachment of GroES to GroEL
induces a conformational change in
the GroEL protein.
The GroEL-GroES complex assists a
protein and achieving its native state.
Conformational
change in GroEL

GroEL-GroES-
assisted folding of
a polypeptide
Binding of GroES to GroEL buries the hydrophobic residues of the GroEL wall
and exposes a number of polar residues
A polypeptide bound to the GroEL wall by hydrophobic interactions is displaced
into the chamber space to continue its folding in a protected environment.
The GroES cap dissociates from the GroEL ring, and the polypeptide is ejected
from the chamber; if the polypeptide is not properly folded, it can rebind to the
same or another GroEL, and the process is repeated.

2.15 | Proteomics and Interactomics
Proteomics
The entire inventory of proteins that is produced by an organism is known as
that organism’s proteome, and is also applied to the inventory of all proteins
that are present in a particular tissue, cell, or cellular organelle.
Proteomics was coined to describe the expanding field of protein biochemistry.
Traditionally, protein biochemists have sought to answer questions about
protein structure, function, and location, one protein at a time.
Proteomics researchers attempt to answer questions on a more
comprehensive scale using large‐scale (or high‐throughput) techniques to
catalog the vast array of proteins produced by a particular cell.

Identifying proteins by
mass spectrometry
Proteomics
Mass spectrometry is a key technique
to determine the precise mass of a
molecule or fragment of a molecule,
which can then be used to identify
that molecule.
The pattern of peaks the MS
constitutes a highly characteristic
peptide mass fingerprint of that
protein, and the protein identity can
then be elucidated from the genomic
sequence of that organism.

Proteomics
Proteomics is playing an increasingly important role in medicine.
Most human diseases may leave biomarkers among the thousands of
proteins present in the blood or other bodily fluids.
The simplest way to find a biomarker protein is to measure the protein’s
interaction with a specific antibody, the basis of the PSA test for prostate
cancer.
Many efforts have been made to compare the proteins present in the blood
of healthy individuals with those present in the blood of persons suffering
from various diseases, especially cancer.
The OVA1 blood test for ovarian cancer, which detects a collection of
biomarkers using antibody‐based tests, was invented using data from
proteomic analysis of a large number of patient samples.

A network of protein–protein interactions.
Interactomics
Global protein–protein interactions
can be determined from a modified
mass spectrometry to produce a
map that shows all of the proteins
that presumably interact inside the
cell.
This complete set of interactions is
called the “interactome” of the cell,
and the results can be presented in
the form of a network.

Protein–protein interactions
of hub proteins.
Interactomics
Proteins that have multiple binding
partners are referred to as hubs of
the protein interaction network.
Hub proteins are more likely to be
essential than non‐hub proteins.
Some hub proteins have several
different binding interfaces capable
of binding a number of different
binding partners at the same time.
Other hubs have a single binding
interface capable of binding several
different partners, but one at a time.

2.16 | Protein Engineering
Current technology allows the making of artificial genes that code
for proteins of specific amino acids sequences.
Knowledge of a protein’s amino acid sequence rarely allows
prediction of a protein’s structure.
The problem is knowing which protein might have some useful
function.
If a computer simulation program could predict the shape a protein
should have to bind to the viral surface of HIV, what sequence of
amino acids strung together would produce such a protein?

Computational design of a
protein that is capable of binding
to the surface of another protein.
Protein biochemists know how to
construct a protein that can bind the
hemagglutinin (HA) protein that was
present in the reconstructed 1918
influenza virus.
This engineered protein is capable of
binding to a hydrophobic patch on the
surface of the HA protein with high
affinity.
The side chains from the designed
protein interact in highly specific ways
with sites on the α helix of HA.

© 2013 John Wiley & Sons, Inc. All rights reserved.
Production of Novel Proteins
It is possible to design and produce artificial proteins capable of catalyzing
organic reactions not catalyzed by any known natural enzyme.
Choose a catalytic mechanism that might accelerate a reaction and use
computer‐based calculations to construct an active site to accomplish it.
Those proteins that show the greatest promise are then subjected to a
process of test‐tube evolution; the proteins are mutated to create a new
generation of altered proteins, which could in turn be screened for
enhanced activity.
Eventually, one could engineer proteins that could accelerate the rates of
reaction as much as one million times that of the uncatalyzed reaction.

© 2013 John Wiley & Sons, Inc. All rights reserved.
Production of Novel Proteins
An alternate approach is to modify those that are already produced by cells.
Site‐directed mutagenesis allows a gene to be mutated in a way that
substitutes an amino acid with different charge, hydrophobic character, or
hydrogen‐bonding properties.
Site‐directed mutagenesis is also used to modify the structure of clinically
useful proteins to bring about various physiological effects.
The drug Somavert, used to treat acromegaly, is a modified version of
human growth hormone (GH) containing several alterations.
Somavert competes with GH in binding to the GH receptor, but interaction
between drug and receptor fails to trigger the cellular response.

Structure-based Drug Design
Another clinical application is the development of new drugs that act by
binding to known proteins to inhibit their activity.
Drug companies have chemical “libraries” with millions of different organic
compounds isolated from plants or microorganisms or chemically
synthesized, which can be screened to see if they bind a protein of interest.
Structure‐based drug design, relies upon knowledge of the structure of the
protein target to design “virtual” drug molecules to render a protein inactive.
The drug Gleevec has revolutionized the treatment of a number of relatively
rare cancers, most notably that of chronic myelogenous leukemia (CML).
The development of CML is driven almost single‐handedly by the presence
of an overactive tyrosine kinase called ABL.

Development of a protein-targeting drug
Researchers identified a compound called 2‐phenylaminopyrimidine that was
capable of inhibiting tyrosine kinases, discovered by randomly screening a
large chemical library for compounds that exhibited this particular activity.
Beginning with this molecule, compounds of greater potency and specificity
were synthesized using structure‐based drug design.
Gleevec was found to bind tightly to the inactive form of the ABL tyrosine
kinase and prevent the enzyme from becoming activated.

Gleevac structure
ABL protein-targeting with
Gleevac (L) and Sprycel (R)
In the very first clinical trial of Gleevec,
virtually all of the CML patients went
into remission after taking once‐daily
doses of the compound; however ABL
kinase can mutate to become resistant
to the drug.
These cancers can be suppressed by
treatment with more recently designed
drugs that are capable of inhibiting
Gleevec‐resistant forms of the ABL
kinase.

Distribution of polar,
charged amino acid
residues in the enzyme
malate dehydrogenase
2.17 | Protein Adaptation and Evolution
Proteins are biochemical adaptations subject
to natural selection and evolutionary change,
and can be compared by evolutionarily related
(homologous) proteins in organisms living in
very different environments.
Homologous proteins can exhibit virtually
identical shapes and folding patterns, but
show strikingly divergent amino acid
sequences.
Secondary and tertiary structures of proteins
change much more slowly during evolution
than their primary structures.

Protein structure alteration from
a single amino acid change.
2.17 | Protein Adaptation and Evolution
An amino acid substitution can completely
alter the conformation of a small domain
within a large protein molecule.
Evolution has produced different versions of
proteins in individual organisms, known as
isoforms, adapted to function in different
tissues or at different developmental stages.
Most proteins are members of much larger
families (superfamilies) of related proteins.
The expansion of protein families is
responsible for much of the protein diversity
encoded in the genomes of today’s complex
plants and animals.

Nucleic acids are polymers of
nucleotides that store and transmit
genetic information.
Deoxyribonucleic acid (DNA) holds
the genetic information in all cellular
organisms and some viruses.
Ribonucleic acid (RNA) is the
genetic material in some viruses.
Nucleotides are connected by 3’-5’
phosphodiester bonds between the
phosphate of one nucleotide and the
3’ carbon of the next.
Nucleotides
and nucleotide
strands of RNA
2.18 | Nucleic Acids

Each nucleotide consists of three
parts: a five-carbon sugar, a
phosphate group, and a nitrogenous
base.
Bases are either purines or
pyrimidines.
The purines are adenine and
guanine in both DNA and RNA.
The pyrimidines are cytosine and
uracil in RNA; uracil is replaced by
thymine in DNA.
Nitrogenous bases in
nucleic acids

RNA is usually single stranded and DNA is usually double stranded.
RNA may fold back on itself to form complex 3D structures, as in ribosomes.
RNA may have catalytic activity; such RNA enzymes are called ribozymes.
Adenosine triphosphate (ATP) is a nucleotide that plays a key role in cellular
metabolism, whereas guanosine triphosphate (GTP) serves as a switch to
turn on some proteins.
RNA and the ribosome

2.19 | The Formation of Complex Macromolecule Structures
The Assembly of Tobacco Mosaic Virus Particles
Can structures that consist of different types of subunits assemble by
themselves?
The most convincing evidence that a particular assembly process is
self‐directed is the demonstration that the assembly can occur outside
the cell (in vitro) under physiological conditions when the only
macromolecules present are those that make up the final structure.
TMV particles, which consist of one long RNA molecule wound within a
helical capsule made of 2130 identical protein subunits, are capable of
self‐assembly.
Mixing purified TMV RNA and proteins can result in infective particles
after a short period of incubation.

2.19 | The Formation of Complex Macromolecule Structures
The Assembly of Ribosomal Subunits
Ribosomes contain several different types of RNA and a considerable
collection of different proteins.
The large (or 50S) ribosomal subunit contains two molecules of RNA and
approximately 32 different proteins. The small (or 30S) ribosomal subunit
of bacteria contains one molecule of RNA and 21 different proteins.
Reconstitution of the small and large subunits of the bacterial ribosome
have been accomplished in vitro.
Although it takes approximately 2 hours at 50°C to reconstitute the
ribosome in vitro, the bacterium can assemble the same structure in a
few minutes at temperatures as low as 10°C.
Assembly of the ribosome within the cell, for example, may include the
participation of accessory factors that function in protein folding.

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