Molecular Structure and

Function
Molecular Structure and
Function

A. Malcolm Campbell, PhD

Christopher J. Paradise, PhD
Molecular Structure and Function
Copyright A. Malcolm Campbell and Christopher J. Paradise. 2016.

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 Abstract
One of the overarching themes in nature is that form meets function,
meaning that the shape of an object determines how well the object can
perform its function. This book begins with some basics about specificity
of shapes and the four increasing levels of protein structure. Most of this
book examines how epinephrine (adrenaline) can cause the liver to release
glucose when a person experiences a fight or flight response. Whenever
someone gets scared, all of their cells are bathed in epinephrine. A subset
of those cells will respond directly to this hormone, and the liver cells
prepare other cells for the extra energy they might need to survive. This
book presents some of the data that revealed how the information of fear
is carried inside liver cells. This book will also consider how and why
some cell membranes are wavy. In short, this book looks at the structure/
function relationship at the molecular level.

Keywords
protein, primary structure, side chains, covalent bonds, ionic bonds,
H-bonds, secondary structures, alpha helices, beta strands, tertiary struc-
ture, quaternary structure, allosteric modulator, covalent modulators,
phosphate, phosphorylation, kinase, signal transduction, receptor, ligand,
G protein, adenylyl cyclase, cAMP, protein kinase, glycogen synthase,
antagonist, transmembrane, double blind trial, placebo effect, endoplas-
mic reticulum, microtubules, kinesin
 Contents
Preface...................................................................................................ix
Acknowledgments....................................................................................xi
Introduction.........................................................................................xiii
Chapter 1 Define Molecular Structure-Function Relationship............1
Chapter 2 Fear Generates Response in Liver Cells...............................7
Ligand Binds to Receptor.................................................11
G-Protein and the Production of cAMP...........................16
Protein Kinase a Functions...............................................18
Phosphorylation Consequences........................................20
Ethical, Legal, Social Implications: Getting New
Drugs to Market Quickly and Safely.............................23
Chapter 3 Importance of Surface Area to Volume Ratio....................29
Conclusion............................................................................................35
Glossary................................................................................................37
Index....................................................................................................39
 Preface
This book on molecular structure and function is part of a thirty book
series that collectively surveys all of the major themes in biology. Rather
than just present information as a collection of facts, the reader is treated
more like a scientist, which means the data behind the major themes are
presented. Reading any of the thirty books by Campbell and Paradise
provides readers with biological context and comprehensive perspective
so that readers can learn important information from a single book with
the potential to see how the major themes span all size scales: molecular,
cellular, organismal, population and ecologic systems. The major themes
of biology encapsulate the entire discipline: information, evolution, cells,
homeostasis and emergent properties.
In the twentieth century, biology was taught with a heavy emphasis
on long lists of terms and many specific details. All of these details were
presented in a way that obscured a more comprehensive understanding.
In this book, readers will learn about the very close relationship between
structure and function at the molecular level with particular attention to
the fear response and the increase of cellular surface area without increas-
ing cell volume. While presenting this information, the book will also
provide some of the supporting evidence behind our understanding. The
historic and more recent experiments and data will be explored. Instead
of believing or simply accepting information, readers of this book will
learn about the science behind structure and function at the molecular
level the same way professional scientists dowith experimentation and
data analysis. In short, data are put back into the teaching of biological
sciences.
Readers of this book who wish to see the textbook version of this
content can go to www.bio.davidson.edu/icb where they will find
pedagogically-designed and interactive Integrating Concepts in Biology for
introductory biology college courses or a high school AP Biology course.
 Acknowledgments
Publishing this book would not have been possible without the generous
gift of Dr. David Botstein who shared some of his Breakthrough Prize
with AMC. Davids gift allowed us to hire talented artists (Tom Webster
and his staff at Lineworks, Inc.) and copyeditor Laura Loveall. Thanks go
to Kristen Mandava for project management and guidance on the pub-
lishing process. In particular, we are indebted to Katie Noble and Melissa
Hayban for their many hours of help and attention to detail.
Kristen Eshleman, Paul Brantley, Bill Hatfield and Olivia Booker
helped us with technology at Davidson College. We are grateful to ad-
ministrators Tom Ross, Clark Ross, Carol Quillen, Wendy Raymond,
Verna Case, and Barbara Lom who had confidence in us and encouraged
us to persist despite setbacks along the way.
These books were the product of the shared labor of my two vision-
ary coauthors Laurie Heyer and Chris Paradise. We shared the dream
and the hardships and developed this book from scratch. My family has
been very supportive and I thank Susan, Celeste and Paulina for their
support and patience. I also want to thank Jan Serie, my pedagogical
mentor, who taught me so much about the art and science of helping stu-
dents learn. I benefited from the support of the Howard Hughes Medi-
cal Institute grant 52006292, the James G. Martin Genomics Program,
and Davidson College. This book would not have survived its first draft
without my students who endured the typos and the early versions of this
book. These undergraduates participated in a bold experiment to see if
beginners could construct their own knowledge, retain what they learned,
and transform the way they see themselves and the discipline of biology.
While many people said that beginning students were not up to the task,
my students proved them wrong.
 Introduction
As the smallest living unit, cells are central to all aspects of biology
and need to be studied for their molecular structure/function relation-
ships. Cells are composed of proteins, lipids, carbohydrates and nucleic
acids. From these building materials, cells assemble organelles in their
cytoplasm. This book considers three aspects of cells at the molecular
level, with special attention to the structures that provide the capacity to
perform functions. Chapter 1 begins with an introduction to protein
folding and the four types of structure used to describe protein shapes.
Shapes determine which specific functions each protein can perform. In
Chapter 2, the reader will study a response to fear to understand how
subcellular molecules work collectively to produce complex responses
that are central to cellular function. Chapter 3 examines why some mem-
branes are wavy and others are smooth. Once again, physics, mathemat-
ics and biochemistry allows scientists to understand why the benefits of
making more membrane outweigh the cost of their production. This book
will use these case studies to bring out overarching themes of biology that
transcend specific examples.
 CHAPTER 1

Define Molecular Structure-

Function Relationship

Chapter 1 sets the stage for the rest of this book. It is important first to
learn about basic protein structure inside cells and how structure affects
function at the molecular level. As has been clearly demonstrated over the
years, ribosomes translate proteins from information encoded in a genome
and proteins can be modified post-translationally. In addition, a protein
contains information in its amino acid sequence that enables it to stay in
the appropriate subcellular location and fold into its appropriate shape. All
proteins possess at least three layers of structural information (Figure 1).
Upon translation, the primary structure of amino acid sequence is suffi-
cient information for proteins to take their final three dimensional shapes.
The chemical properties of a protein are determined by the side
chains, those atoms above the universal amino acid backbone of
H3N+CHCOO (Figure 2). Chemical interactions of side chains can
lead to secondary through quaternary structure as seen in Figure 1. Any
atom can participate in the strongest chemical bondscovalent bonds,
in which the two atoms share electrons. Only five amino acids, the acids
and bases, can participate in ionic bonds between their side chains. The
other six hydrophilic amino acids can participate in the very weak
hydrogen bonds, H-bonds. Note that all of the hydrophilic amino acids
terminate in one of the four biologically common elements that are elec-
tronegative and tend to pull electrons closer to their nuclei: nitrogen,
oxygen, phosphorous, and sulfur (abbreviated N O P S). As the side
chains begin to interact with each other and water within the cytoplasm,
the snakelike proteins begin to bend and fold to maximize the stabil-
ity of the large molecule. Hydrophobic amino acids tend to accumulate
in oily pockets that exclude water and hydrophilic amino acids. With
2 MOLECULAR STRUCTURE AND FUNCTION

MFGRYTWASDCGNMMN
KLPIKHAASDWQTYJA
MHA....LERWTQIPL

A B

C D

Figure 1 Four levels of protein structure. A, Primary structure

of amino acid sequence within a protein. B, Amino acids fold into
secondary structures, which are illustrated in two ways, either as
curvy lines, or as three beta stands (arrows) and one alpha helix.
C, Tertiary structure consists of all secondary structures as well
as any other shapes adopted by the entire protein. D, Quaternary
structure is present only when two or more proteins come together to
form a single functional protein complex. Three proteins in shades of
gray, and a ligand (series of spheres) are shown here.
Source: Original art.

this first layer of folding, some characteristic shapes become apparent and
are called secondary structures (Figure 1B). Spiral alpha helices and
zigzagging beta strands form as a result of weak H-bonds between the
universal backbones of amino acids aligned in just the right pattern due
to the chemical properties of their side chains. Every different protein has
its own combination of alpha helices and beta strands as determined by
the proteins primary structure. It is important to to understand proteins
in order to understand the function of cells. Protein structure determines
its function, which in turn determines the function of every cell on earth.
 Define Molecular Structure-Function Relationship 3

A H H
C C
H3C H
C HC CH
H CH3 CH3 S HC CH
H3C
H CH3 C H CH3 H2 H2C HN
H3C H2C HC
CH3 C CH2 C C H2 CH2 C CH2 C CH2
C
H2 H2C H H
C O C O C O C O C O C O C O C O C O
H3N+ H3N+ H3N+ H3N+ H3N+ N H H3N+ H3N+ H3N+
O O O O O O O O O
glycine alanine valine leucine isoleucine proline methionine phenylaline tryptophan

B HO
H
C H 2N
CH O
O
HO H OH HS H2 C
HC H3C
C CH2 CH2 C CH2 H2 N CH2 CH2
H
C O C O C O C O C O C O
H3N+ H3N+ H 3 N+ H3N+ H3N+ H3N+
O O O O O O
tyrosine serine threonine cysteine asparagine glutamine

H2N
+
NH3 N+H2
H H2C HN O
C N+H CH2 CH2 O
O
HN H2C H2C H2 C
C CH2 CH2 CH2 O CH2 CH2
H
C O C O C O C O C O
H3N+ H3N+ H3N+ H3N+ H3N+
O O O O O
histidine lysine arginine aspartic acid glutamic acid

Figure 2 Amino acid physical and chemical properties. A, Nine

amino acids have side chains that contain only carbon and hydrogen
and therefore are hydrophobic, such as water beading up on a waxed
floor. B, Eleven amino acids contain either nitrogen, oxygen, or sulfur
at the extreme ends of their side chains and are hydrophilic. Three
have side chains with positively charged bases (left) and two have
side chains with negatively charged acids (right) participate in ionic
bonds (magnet icon), and the remaining six can participate in weak
hydrogen bonds (sticky note icon).
Source: Original art.

After the secondary structures self-assemble in a newly produced protein,

the amino acids continue to wiggle inside a cell to further stabilize the
proteins overall structure. New folds, hydrophobic interactions, as well
as ionic and hydrogen bonds will form, producing the tertiary structure,
which is the overall three-dimensional shape of the protein. If a protein
assembles with two or more proteins, then the collection of proteins ac-
cumulates quaternary structure, which is the result of the individual
proteins interacting based on their already established tertiary structure.
Every protein contains primary, secondary, and tertiary structure, and
some will form quaternary structure described in Chapter 2.
It is important to understand protein structure because the shape of a
protein determines its function, and proteins are responsible for many, if not
most, of a cells daily activities. However, protein structure is not static. In ad-
dition to the normal wiggling of molecules due to the vibration of all atoms,
4 MOLECULAR STRUCTURE AND FUNCTION

protein shape can be affected by two types of modifications. One category

of shape modifier is called an allosteric modulator. Allosteric modulators
can be any size, from large molecules to tiny chemical ions, such as calcium
(Ca2+) or sodium (Na+). Allosteric interactions between the modulator and
its target protein do not involve covalent bonds. Instead, weak interactions
of ionic and hydrogen bonds allosterically modulate protein structure. If a
proteins structure is changed, so is its function. There are very few firm rules
in biology, but one very important rule is change of shape, change of func-
tion. Allosteric modulators bind temporarily to their target proteins and
eventually wiggle away. If the modulator is not replaced by another one, the
protein reverts back to its prior shape and previous function.
Covalent modulators, as the name implies, attach to proteins by
covalent bonds. A very common covalent modulator is the phosphate
group (PO4), which must be connected to amino acids in the protein via
terminal hydroxyl groups (OH). Phosphorylation of a protein brings a
full negative charge to the surface of a protein, which will quickly affect
the proteins shape. It is impossible to predict in advance if phosphoryla-
tion will enhance or reduce a proteins ability to function, but the func-
tion will change. As with most biochemical reactions inside cells, enzymes
catalyze new covalent bond formation. Kinase enzymes catalyze phos-
phorylation of proteins. Creating a new covalent bond requires energy,
so kinases must be able to bind and consume an adenosine triphosphate
(ATP) every time they phosphorylate their targets. The terminal phos-
phate of ATP is bound to the protein as the covalent modulator with
ADP a waste product of the phosphorylation. Cells do not perform the
same function all the time, and therefore they need ways to alter the func-
tion of their constituent proteins. Allosteric and covalent modulation are
the most common mechanisms to change a proteins shape and its func-
tion, allowing cells to respond to changes in their local environments.
In addition to protein structure and its impact on cellular function,
it is important to know the impact of subtle chemical shape differences
within a cell (Figure 3). When a person eats, it is easy to detect the
difference between celery and potatoes. A plain, large baked potato
contains about 300 calories, as do other sources of starch, such as pasta
and rice. An equivalent weight of celery yields only 30 calories in humans.
This caloric difference probably is not a surprise, but most people are
 Define Molecular Structure-Function Relationship 5

6
CH2OH
6 6 6 5 O
CH2OH CH2OH CH2OH 4
5 5 5 OH 1
O O O O 2
4 OH 1 4 OH 1 4 OH 1 OH
3
2 O 2 2 OH
OH 3 OH OH 3
3
OH OH OH


Figure 3 Differences in glucose polymers. Potatoes rich in starch (left),
which is made by connecting glucose molecules via ` 1-4 covalent
bonds. Celery is a mixture of water and cellulose (right) in its plant
cell walls. Cellulose is a polymer of glucose connected by a 1-4 covalent
bonds. Carbons are located at the vertices and are numbered 1-6.
Source: Original art.

surprised to learn that celery and potatoes are both composed of the same
six-carbon sugar called glucose. Celery, cotton, and paper are made of the
glucose polymer cellulose, but people cannot get fat eating them. In fact,
the only fattening part of a salad is what people add to the lettuce. Why
are starch and cellulose polymers so different when they are both com-
posed of glucose? The difference is in the subtle details of chemical bonds
(Figure 3). The glucose polymer of starch is used by plants and animals
as a source of glucose and energy. In starch, glucose is connected by
1-4 covalent bonds that connect carbon #1 of one glucose to carbon
#4 of its neighbor. The 1-4 linkages connects hundreds of glucose
molecules per starch molecule. Many animals make a different glucose
storage molecule called glycogen, which is stored in the liver. In cellu-
lose, however, glucose is connected by 1-4 covalent bonds that connect
the same two carbon atoms but at a different angle. Human cells have
enzymes that can break down starch but cannot digest cellulose because
1-4 covalent bonds do not match the shape of human enzymes as de-
termined by their primary, secondary, and tertiary structure.
Now the stage is set to learn more about protein shape and function,
as well as the specificity of enzymes for their substrates. All of these top-
ics are central to understanding how molecules change shape in response
to fear which is the subject of Chapter 2. Molecules cannot understand
that a shark or snake is dangerous, but through molecular shape changes,
people can mobilize glucose from their livers and tell their muscles to get
6 MOLECULAR STRUCTURE AND FUNCTION

away from danger. Chapter 2 facilitates understanding how liver cells use
molecular protein shapes to respond to fear by providing the entire body
with enough energy to respond to dangerous situations and perhaps save
a persons life. Natural selection has favored individuals whose proteins
are responsive to subtle chemical differences.
Proteins typically contain all twenty amino acids, but only three can
be covalently modified by kinases. Because phosphates require terminal
OH groups on amino acid side chains, only serine, threonine, and tyro-
sine are suitable substrates for kinases. Based on their structures as shown
in Figure 2, it can be seen that some kinases specialize in phosphorylating
either serine or structurally similar threonine, whereas a different class of
kinases phosphorylates the much larger tyrosine side chain. Kinases have
active sites that fit particular amino acid substrates. As is often the case at
the molecular level, a particular size of an active site does not fit all amino
acids. Proteins that are allosterically modulated often interact through
weak ionic bonds or weaker H-bonds. Some allosteric modulators are
hydrophobic, and they bind to their target proteins via hydrophobic side
chains. Hydrophobic interactions can be disrupted by detergents or hy-
drophobic solvents, such as oils. Covalent modulation, however, is much
more durable and is typically removed only when an enzyme, such as a
phosphatase, breaks the bond holding the phosphate in place.
Nearly everywhere one looks at the molecular level, cells are regulated
by the three-dimensional shapes of proteins. Although wood and starch are
both plant polymers composed of glucose, only microbes contain the en-
zymes necessary to digest 1-4 covalent bonds. Because human genomes do
not encode the same enzymes as other species, humans consider lettuce to
be roughage, whereas other organisms can extract many calories from cellu-
lose. As this book explores cellular structure and function, pay attention the
molecular shape of proteins and how they change, because change of shape
leads to a change in function. Chapter 2 uses one example to show how fear
leads to a series molecular shape changes that are a matter of life and death.

Bibliography
Anfinsen CB.1973. Principles that govern the folding of protein chains
(Nobel Lecture).Science 181(4096): 223230.
 Index
Adenosine triphosphate (ATP), 4
Adenylyl cyclase, 10, 1718
Adrenaline. See Epinephrine
-adrenergic receptors, 14, 15
Allosteric modulator, 4
Amino acids, physical and chemical
properties, 3
Covalent bonds, 1
Covalent modulators, 4
Cytoskeleton, 29
Double blind trial, 24
Endoplasmic reticulum (ER), 30
Epinephrine, 7
ethical, legal, social
implications,2326
fear signal transduction pathway
from, 9
liver injected with, 1112
pathway from, 8
receptor, structure of, 1415
and two antagonists, 1314
Food and Drug Administration
(FDA), 24
G protein, 10
GDP, 1617
Gefitinib (Iressa), 25
Glucose polymers, 5
Glycogen, 5
production of glucose from in
liver,22
synthase, 10
structure and degradation, 13
G-protein, production of
cAMP,1618
four step cycle of activation, 16
Human plasma membranes, 3132
Hydrophobic amino acids, 12
Immunofluorescence, 23
Ionic bonds, 1
Kinase enzymes, 4
Kinesin, 31
Lipid composition, shapes of cell
membranes, 3133
Liver
injected with epinephrine, 1112
production of glucose from
glycogen in, 22
Microtubules, 3031
Microvilli, 30
Molecular structure-function
relationship, definition
of,16
Non-small cell lung cancer, 25
Phosphate group (PO4), 4
Phosphorylase kinase, 10, 20
slower activation process
of, 21
Phosphorylation, 4
consequences of, 2023
Placebo effect, 24
Protein kinase A (PKA), 10
functions of, 1820
40 INDEX
Protein
chemical properties of, 1
and impact on cellular function, 4
quaternary structure of, 3
structure inside cells, 1
types of modifications, 4
Quaternary structure of protein, 3
Receptor, ligand binds to, 1115
Rofecoxib (Vioxx), 2526
Secondary structures of proteins, 2
Signal transduction, 8, 2122
Surface area to volume ratio, 2933
Tertiary structure of protein, 3
 OTHER TITLES IN OUR BIOLOGY
COLLECTION

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Cellular Consequences of Evolutionby A. Malcolm Campbell and Christopher J. Paradise
Cellular Respirationby A. Malcolm Campbell and Christopher J. Paradise
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Evolution and Origin of Cellsby A. Malcolm Campbell and Christopher J. Paradise
Reproduction and Cell Divisionby A. Malcolm Campbell and Christopher J. Paradise
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Cell Networksby A. Malcolm Campbell and Christopher J. Paradise
Molecular Switchesby A. Malcolm Campbell and Christopher J. Paradise
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