Urry D.W. (Ed.) What Sustains Life? : Consilient Mechanisms for Protein-Based Machines and Materials

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2.8 "What Sustains Life?" Becomes "What Sustains Society?"

bioelastic matrix stimulates the appropriate

attached cells to produce their own extracellu-

lar matrix, that

is,

to begin the reconstruction of

a natural, functional tissue as shown in a simu-

lated urinary bladder system."^"^

Thus,

the potential exists for preparing bioe-

lastic matrices that match the deformable prop-

erties of the tissue to be reconstructed, and the

potential exists for the matrix to be a tempo-

rary functional scaffolding into which the

natural cells migrate and attach. There the cells

sense the forces that the tissue must sustain and

begin reconstructing the appropriate natural

tissue.

2.8.3 Drug Delivery

In one design for drug delivery, the drug itself

provides the chemical energy to drive folding

and contraction, that is, the drug provides the

energy for its own packaging into the drug

delivery vehicle. When the model protein con-

tains negatively charged carboxylates under the

influence of oil-like R-groups, the affinity for a

positively charged drug increases just like the

affinity increases for

protons.

Therefore, instead

of adding proton, the positively charged drug is

added to drive folding and contraction. The

model protein separates out of solution holding

the drug firmly to form the drug delivery

vehicle. As the drug leaves the vehicle so too

does the vehicle disperse. In effect, the drug

provided the glue that held the delivery device

together.

Many of the drugs that control pain, for

example, the narcotics, are positively charged.

The body has its own painkillers, referred to as

endorphins', these are naturally released by the

body after about 20 to 30 minutes of running

and are considered responsible for the runner's

high. An active part of the endorphins are

the enkephalins. One, called Leu-enkephalin

amide, is positively charged and has been

loaded into a designed model protein with a

strong oil-like sequence and with a carboxylate

occurring every 15 amino acid residues, as

shown in Figure 2.21. The release of this posi-

tively charged drug from a constant surface

area in a test tube is shown in Figure 2.21 to

maintain a near constant release for 3 months.

Release extending out to a year has now been

demonstrated.

With respect to control of drug addiction, the

positively charged narcotic antagonist naltrex-

10.0

5.0

0.0

Release Profiles of Leu-enkephalin amide from

Glu-containing Protein-based Polymers

250 mg polymer

loading conditions: pH 6.8

1.5 equivalents of

drug

for

each Glu binding site

poly(GFGFP GEGFP GFGFP)

*•••

•••••^

1.85 [imole

20 40

60 80 100

days

FIGURE

2.21.

The designed elastic-contractile model vehicle and to control the release level. See text and

proteins function by means of the apolar-polar Chapter 9 for further discussion. (Reproduced from

repulsive free energy of hydration to achieve zero Urry et al."*^)

order release with simultaneous dispersal of delivery

What Sustains Life? An Overview

one,

when in the blood, blocks the action of a

millionfold higher dose of heroin. An addict

with naltrexone in the bloodstream receives

no high from heroin. Therefore, a controlled

release of naltrexone from an implant in the

body to the bloodstream of an addict, after

withdrawal, would guard against return to

dependency.

2.8.4 Smart Plastics

A smart plastic would harmlessly disintegrate

once its useful Life were completed. Plastics

made of plastic-contractile model proteins with

controllable inverse temperature transitions

can be designed as smart plastics. A smart

protein-based plastic, having fulfilled its role,

would swell and become a fragile, edible

gelatin-like substance. Rather than foretell

death for the fishes, a smart protein-based

plastic could provide food for the fishes, once

its useful Life as a plastic were complete.

The natural amino acids asparagine and glu-

tamine provide chemical clocks for the disinte-

gration of protein-based plastics; they have the

R-groups -CH2CONH2 and -CH2CH2CONH2,

respectively. The carboxamide functional

group, -CONH2, hydrolyzes to negatively

charged carboxylates, -COO", at predesigned

rates.

Half of the carboxamides will convert to

carboxylates in as short a time as a few days or

in as long a time as 10 years. The time can be

set by the choice of the amino acid residues

immediately preceding and following in the

sequence and by the general oil-like character

of the model protein. The desired half-life can

be designed into the sequence of the protein-

based plastic. As the carboxylates form from

carboxamides at the surface, the plastic swells

to a fragile, edible gel. Protein-based plastics

could become food for marine life.

Examples of protein-based plastics with

transition temperatures below 0°C are given in

Figure 2.22 and Figure 1.10; they remain strong

plastics in water until the chemical clocks, that

is,

the timed conversion of carboxamides to car-

boxylates, raise the transition temperature from

below to above the temperature of the water.

At this point, the plastics, having fulfilled their

useful life, gracefully soften and disappear.

FIGURE

2.22. By changing one of the Gly residues of

GVGVP to an L-amino acid residue, for example, to

AVGVP, resuks in a new family of model proteins

that become programmably biodegradable inverse

thermoplastics. The three examples given are

poly(FVGVP), poly(IVGVP), and poly(VvGVP).

(D.W. Urry and D.C. Gowda, unpublished results.)

References 67

References

D.W. Urry, "Elastic Biomolecular Machines: Syn-

thetic Chains of Amino Acids, Patterned After

Those in Connective Tissue, Can Transform Heat

and Chemical Energy into Motion." Sci. Am.

January 1995, 64-69.

Vinegar is a solution primarily of acetic acid,

CH3COOH, and water. As shown by Pasteur in

1864,

vinegar is made from alcohol by certain

bacteria under aerobic conditions.

C.B. Anfinsen, "Principles that Govern the

Folding of Protein Chains." Science, 181,

223-230,1973.

D.W. Urry, "Protein Folding and the Movements

of Life." The World & /, (Natural Science, At The

Edge),

6, 301-309,1991.

A. Szent-Gyorgyi, "Studies on Muscle." Acta

Physiol.

Scand.,

9 (suppl XXV), 1-116,1945.

6. D.W. Urry, "Molecular Machines: How Motion

and Other Functions of Living Organisms Can

Result from Reversible Chemical Changes."

Angew. Chem. (German) 105, 859-883, 1993;

Angew. Chem. Int. Ed. Engl., 32, 819-841,1993.

D.W. Urry, "Physical Chemistry of Biological

Free Energy Transduction as Demonstrated by

Elastic Protein-based Polymers," invited Feature

Article, / Phys. Chem. B, 101, 11007-11028,

1997.

8. C.S. Roy, "The elastic properties of the arterial

wall." /. Physiol, 3,125-159,1880.

9. D.W. Urry and T.M. Parker, "Mechanics of

Elastin: Molecular Mechanism of Biological

Elasticity and its Relevance to Contraction." /.

Muscle Res. Cell Motil., 23,541-557,2002; Special

Issue, Mechanics of Elastic Biomolecules. H.

Granzier, M. Kellermayer, W Linke, Eds.

10.

L.B. Sandberg, N.T Soskel, and J.B. LesUe,

"Elastin Structure, Biosynthesis and Relation to

Disease States." A/:£ng/./.Me^.,304,566-579,1981.

11.

H. Yeh, N. Ornstein-Goldstein, Z. Indik, P

Sheppard, N. Anderson, J.C. Rosenbloom, G

Cicila, K. Yoon, and Rosenbloom, "Sequence

Variation of Bovine Elastin mRNA Due to

Alternative Splicing." J. Collagen Rel. Res., 1,

235-247,1987.

12.

It has now been possible to stretch a single

elastic protein-based polymer chain and to

obtain a uniformly increasing force versus exten-

sion curve.

^^'^"^

This was done with a surprisingly

simple device called an atomic force microscope,

the development of which resulted in the Nobel

prize for Paul Hansma. The performance of the

mechanical work of lifting a weight, shown in

Figure 2.4, utilized one-sixteenth of an inch thick

and one-fourth of an inch wide elastic bands. We

are now working to develop twisted filaments of

some three chains about a millionth of an inch

wide to perform similar energy conversions.

13.

D.W. Urry,T. Hugel, M. Seitz, H. Gaub, L. Sheiba,

J. Dea, J. Xu, and T. Parker, "Elastin: A Repre-

sentative Ideal Protein Elastomer." Philos. Trans.

Soc.

Lond.

B, 357,169-184, 2002.

14.

D.W. Urry,T. Hugel, M. Seitz, H. Gaub, L. Sheiba,

J. Dea, J. Xu, L. Hayes, F. Prochazka, and T.

Parker, "Ideal Protein Elasticity: The Elastin

Model." In Elastomeric Proteins: Structures,

Biomechanical Properties and Biological Roles.

PR. Shewry, A.S. Tatham, and A.J. Bailey, Eds.

Cambridge University Press, The Royal Society;

Chapter Four, pages

54-93, 2003.

15.

E.O. Wilson, Consilience: The Unity of Knowl-

edge. Alfred E.

Knopf,

New York, 1998, p. 8.

16.

D.W. Urry, M.M. Long, and H. Sugano, "Cyclic

Analog of Elastin Polyhexapeptide Exhibits

an Inverse Temperature Transition Leading to

Crystallization." /. Biol. Chem., 253, 6301-6302,

1978.

17.

M.V. Stackelberg and H.R. Muller, "Zur Struk-

tur der Gashydrate." Naturwissenschaften, 38,

456-458,1951.

18.

D.W. Urry, S.Q. Peng,

Xu, and D.T. McPherson,

"Characterization of Waters of Hydrophobic

Hydration by Microwave Dielectric Relax-

ation." /. Am. Chem. Soc, 119,1161-1162,1997.

19.

Entropy measures the change in order; a positive

change in entropy measures increased disorder,

and a negative change in entropy measures

increased order. For the transition where ice

melts to form water at 0°C (273°K on the

absolute scale where motion ceases at 0°K), the

increase in entropy is the experimentally deter-

mined heat absorbed during the transition

divided by the temperature for the transition,

that

is,

273°K (see Chapter 5 for a more complete

discussion).

20.

E. Schrodinger, What is Life? Cambridge

University Press, Cambridge, England, first

published in 1944, Canto edition with "Mind

and Matter" and Autobiographical Sketches,

Forward by R. Penrose, 1992.

21.

It should be recognized that a change in entropy,

AS,

is a readily determined experimental quan-

tity.

The measured heat of the transition, AH, the

heat in calories required to drive the folding rep-

resented in Figures 2.1 and 2.2, is simply divided

by the temperature,

Tt,

at which the folding tran-

sition occurs, that is, AH/Tt = AS.

What Sustains Life? An Overview

22.

J.A.V. Butler, "The Energy and Entropy

of Hydration of Organic Compounds." Trans.

Faraday Soc, 33,229-238,1937.

23.

Commonly for elastic contractile model proteins

in aqueous solutions, the magnitude of the

decrease in the transition temperature,

Tt,

is pro-

portional to the negative entropy change for the

transition. The increased hydrophobicity that

lowers Tt translates into a greater exothermic

heat change, AHt, for the transition, that is,

AHt(after) - AHt(before) is a negative quantity.

The measure of the entropy change for the tran-

sition,

ASt,

is simply

AHt/Tj.

Within this measured

increase in entropy for the system of model

protein plus water, however, is a negative

entropy change due to the increase in order

resulting from model protein folding and assem-

bly. Thus, the energy sources that effect energy

conversion by this mechanism do so by means of

increasing negative entropy to the model protein

part of the system.

24.

For more details, see, for example, D. Voet, J.G.

Voet, and C.W Pratt, Fundamentals of Biochem-

istry. John Wiley & Sons, New York, 1999, pp.

529-561.

25.

The structure of the functional component of the

nicotinamides of photosynthesis and respiration

that undergoes oxidation and reduction is given

in Figure 3.6.

26.

For more details, see, for example, D. Voet, J.G.

Voet, and C.W. Pratt, Fundamentals of Biochem-

istry. John Wiley & Sons, New York, 1999, pp.

492-528.

27.

As is now taught in middle school, living organ-

isms oxidize glucose to produce the chemical

energy of ATP, the universal energy currency of

biology, whereas in our fireplaces the burning of

wood, which is the oxidation of cellulose, a

polymer of the same glucose molecule, provides

thermal energy for heating our homes.

28.

D.W. Urry, L.C. Hayes, and D. Channe Gowda,

"Electromechanical Transduction: Reduction-

driven Hydrophobic Folding Demonstrated in a

Model Protein to Perform Mechanical Work."

Biochem. Biophys. Res. Commun., 204, 230-237,

1994.

29.

A. Pattanaik, D. Channe Gowda, and D.W. Urry,

"Phosphorylation and Dephosphorylation Mod-

ulation of an Inverse Temperature Transition."

Biochem. Biophys. Res. Commun., 178, 539-545,

1991.

30.

D.W. Urry, D. Channe Gowda, S.Q. Peng, and

TM. Parker, "Non-linear Hydrophobic-induced

pKa Shifts: Implications for Efficiency of Con-

version to Chemical Energy." Chem. Phys. Lett.,

239,

67-74,1995. A millionfold increase in affin-

ity is what would be required for pumping

protons into the stomach.

31.

D.W. Urry, L.C. Hayes, D. Channe Gowda, S.Q.

Peng, and N. Jing, "Electrochemical Trans-

duction in Elastic Protein-based Polymers."

Biochem. Biophys. Res. Commun., 210,

1031-1039,1995.

32.

For more general details, see, for example, D.

Voet, J.G. Voet, and C.W. Pratt, Fundamentals of

Biochemistry. John Wiley & Sons, New York,

1999,

pp. 180-186. Muscle contraction is also

treated in some detail in Chapter 8.

33.

Mitchell, "Keilin's Respiratory Chain Concept

and its Chemiosmotic Consequences." Science,

206,1148-1159,1979.

34.

I.Z. Steinberg, A. Oplatka, and A. Katchalsky,

"Mechanochemical Engines." Nature, 210,

568-571,1966.

35.

Interestingly, on the basis of the differences in

the

AGHA

values for the Asp-COOH and Asp-

COO"

in Table 5.3, protonation causes Asp to

become more oil-like and to seek out an oil-hke

site such as the lipid bilayer of the thylakoid and

inner mitochondrial membranes. The change in

AGHA

values times ten gives the calculated

energy input for the transport of ten protons to

drive one complete rotation of the Fo-motor,

which would be

kcal/mol-rotation. As a single

rotation of the Fo-motor can synthesize three

ATP molecules from ADP plus Pi, the chemical

energy output would be 24 kcal/mol-rotation,

which gives a maximum possible efficiency of

100x24/38 or 63%.

36.

D.W. Urry, "Free Energy Transduction in

Polypeptides and Proteins Based on Inverse

Temperature Transitions." Prog. Biophys. Mol.

Biol., 57,23-57,1992.

37.

D.M. Himmel, S. Gourinath, L. Reshetnikova, Y.

Shen, A.G. Szent-Gyorgyi, and C. Cohen, "Crys-

tallographic Findings on the Internally Uncou-

pled and Near Rigor States of Myosin: Further

Insights into the Mechanics of the Motor." Proc.

Natl.

Acad.

ScL U.S.A., 99,12645-12650,2002.

38.

It is a particular pleasure to point out in this

context that Andrew G. Szent-Gyorgyi is the son

of Albert Szent-Gyorgyi, the notable of section

2.2.1 who was perhaps the first person to see the

motion of Life outside of the living organism,

when he isolated actomyosin and added the

chemicals to cause contraction.^

39.

A.R. Fersht, "The Charging of tRNA," In Accu-

racy in Molecular Processes: Its Control and Rel-

References 69

evance to Living Systems, T.B.L. Kirkwood, R.F.

Rosenberger, and D.J. Galas, Eds., Chapman and

Hall, London, 1986, pp. 67-82.

40.

D.W. Urry and H. Eyring, "Stereochemistry

and Rate Theory in Protein Synthesis." Arch.

Biochem. Biophys., Suppl. 1, 52-62,1962.

41.

J. Bronowski, The Ascent of Man. Little, Brown

and Company, Boston/Toronto, 1973, p. 110.

42.

D.T. McPherson, J. Xu, and D.W. Urry, "Product

Purification by Reversible Phase Transition Fol-

lowing E. coli Expression of Genes Encoding up

to 251 Repeats of the Elastomeric Pentapeptide

GVGVP." Protein Expression Purification, 7,

51-57,1996.

43.

D.W. Urry, D.T. McPherson, J. Xu, H. Daniell, C.

Guda, D.C. Gowda,

Jing,T.M.

Parker, "Protein-

based Polymeric Materials: Syntheses and Prop-

erties."

In The Polymeric Materials Encyclopedia:

Synthesis, Properties and Applications, CRC

Press,

Boca Raton, pp. 7263-7279,1996.

44.

D.W. Urry and A. Pattanaik, "Elastic Protein-

based Materials in Tissue Reconstruction." Ann.

N.Y.Acad ScL, 831, 32-46,1997.

45.

D.W. Urry, "Engineers of Creation," Chemistry

in Britain, 32, 39-42,1996.

46.

Dan W. Urry, "Elastic Molecular Machines in

Metabolism and Soft Tissue Restoration,"

TIBTECH,

17,249-257 (1999).

47.

N. Wang, IP Butler, and D.E. Ingber, "Mechan-

otransduction across the cell surface and

through the cytoskeleton." Science, 260,

1124-1127,1993.

48.

D.W. Urry, A. Pattanaik, M.A. Accavitti, C-X.

Luan, D.T. McPherson, J. Xu, D.C. Gowda, TM.

Parker, CM. Harris, and N. Jing, "Transductional

Elastic and Plastic Protein-based Polymers as

Potential Medical Devices," in Handbook of

Biodegradable Polymers, ed. by Domb, Kost, and

Wiseman, Harwood Academic Pubhshers, Chur,

Switzerland, pp. 367-386,1997.

The Pilgrimage: Highlights in Our

Understanding of the Products and

Components of Living Organisms

3.1 Initial Glimpses

3.1.1 The First Ionian Enlightenment:

Thales of Miletus

Historians point to a defined

period,

place,

and

person where began the ascent of man toward

an empowering understanding of

his

world.^ The

period was the 6th century

BC.

The place was

Miletus on the Aegean Sea in greater Greece,

and the person was Thales. In the 6th century

before the birth of Christ, Thales of Miletus

forged the first Ionian revolution and began dis-

peUing the illusions of knowledge embodied

in Greek mythology. No longer would myth

unchallenged provide an acceptable explana-

tion of natural phenomena. No longer would

Hesiod's accounts of the Greek Gods—Chaos,

Gaea (Earth), and Eros (Desire); and of Gaea's

giving

birth to the Heavens (Uranus), the Moun-

tains,

and the Sea (Pontus)—satisfy the desire

for understanding nature.

In its place Thales of Miletus launched the

sense of inquiry with the simple question,

"What is the world made of?" His simple

rejoinder "water" has been given explanation;

Thales of Miletus reasoned "that the principal

is water... getting the notion perhaps from

seeing that the nutriment of all things is moist

and kept alive by it... and from the fact that

the seeds of all things have a moist nature and

that water is the nature of moist things."^

As regards living things and as advanced in

this volume, water is the vital ingredient that

uniquely enables efficient function of biomo-

lecular machines. Water dissolves the more

polar parts of chain biomolecules and, in a

uniquely constrained way, transiently hydrates

"water-insoluble" oil-like parts of biomolecules

in a molecular interplay that powers protein-

based machines. Biomolecular machines

sustain Life, and, in an analogous manner,

man's machines sustain society. The require-

ments for sustaining both Life and society

necessitate access to adequate energy sources.

3.1.2 Staying the Prediction

of Malthus

1798,

Thomas Robert Malthus, in "An Essay

on the Principle of Population" made two

postulates: "First, That food is necessary to the

existence of man. Secondly, That the passion

between the sexes is necessary and will remain

nearly in its present state."^ Malthus then

expanded upon his postulates: "I say that the

power of population is indefinitely greater

than the power in the earth to produce subsis-

tence for man. Population, when unchecked,

increases in a geometrical ratio. Subsistence

increases only in an arithmetic ratio."

Malthus further argued, "The race of plants

and the race of animals shrink under this great

restrictive

law.

And the race of man cannot, by

any efforts of reason, escape from it. Among

plants and animals its effects are waste of

seed, sickness, and premature death. Among

mankind, misery and vice." How then has the

world for 200 years stayed the prediction of

Malthus?

3.1 Initial Glimpses

How does the earth sustain populations

greater and standards of living higher than con-

ceivable to Malthus? Machines and the ener-

gies that power them sustain Life and sustain

society. Technological developments hold back

the most disastrous devastations and derive

sustenance from the earth and sun to provide

standards of living beyond comprehension

200 years ago. By way of illustration, western

technological advancements, descendent from

that first Ionian revolution, find the oil, pump

the oil out of the earth's crust, refine the oil,

design the oil-powered machines, and thereby

provide the energy that power the machines

and increase the earth's capacity to sustain

society.

By acquiring sufficient energy resources to

fuel the molecular machines of biology (to

provide food sources) and to fuel the man-

made machines of society, technology has

stayed the Malthusian catastrophe. Popular

energy resources are not limitless, however, and

associated pollutions increasingly challenge

our biosphere. In this volume, we examine the

biomolecular machines of Life and then, in an

as yet very preliminary way, explore specific

means whereby efficient, environmentally

friendly biomolecular machines may help

sustain society.

3.1.3 A Process for Obtaining

Meaningful Answers

Beyond asking a meaningful question follows a

process for determining a meaningful answer.

That process has become known as the scien-

tific

method.

At a fundamental level the

Periodic Table of the Elements answers the

question posed 26 centuries earlier by Thales of

Miletus. Mendeleev formulated the periodic

law for the elements circa 1870 (see Figure 3.1),

yet decades passed before this foundation of

chemical theory became generally accepted.

Successful prediction and subsequent verifica-

tion of additional elements not known in 1870

resulted in general acceptance and the estab-

Ushment of the periodic law as represented in

the Periodic Table of the Elements of Nature

TA BELLE 11

GRgPPCl.

—

R20

Hsi

mxm

(Cus63)

Rb-8S

(Agstoe)

CS=I33

C-)

—

(Au~i99)

I"-

GRUPPe 11.

—

B»«9,4

MQ«24

C<1*40

Zn«65

Sr^ST

Cd«li2

90*137

—

200

GRUPPC III.

—

R20^

m^m

"mm::^

-=44

-*68

?Yt S88

ln=ll3

TOi= 138

—

?Er«l78

Tf «204

•"

GRUPPE W.

RH*

R02

C«>2

$1*28

T;*48

~»72

Zi'«90

Sn*tl8

?Ces|40

—

to*

180

Pb»207

Th»23l

GRUPPE V.

RH5

R205

N*14

P«3l

V=51

As a 75

Nbs94

Sb>l22

—

T0» 182

Bi * 208

GRUPPE VI.

RH2

R03

0»»6

S»32

Cr=52

SC *78

Mo>98

Te«l25

W«i84

U»240

GRUPPE VU.

R207

F«I9

Ci«35.5

Mn*59

--I00

J«I27

—

,—

GRUPPE vm.

—

R04

Fe = 58.C«= 59,

Nis 59, Cu*63.

Ru*l04, Rha|04,

Pd>l06. Aqs.|08.

0$ = I95.tr = 197,

Pt = 198.

Au =

l99

mmmm

MIM

.M.

^mm

•

centuries passed before Mendeleev answered, in part, the question of

Thales

of Miletus.

• Meaningful questions giving rise

experiments that lead

meaningful answers with verifiable

predictions

become the

foundation of scientific inquiry.

• Verifiable predictions

become

empowering results

which

science

and societies advance.

FIGURE 3.1. The Periodic Table of the Elements:

Mendeleev's last version as proposed in 1871-1872

with spaces left for elements that he deduced existed

but that were unknown at the time. This provides a

substantive answer to the question posed by Thales

of Miletus and in doing so constitutes the beginning

of one of the most fundamental systematizations of

science. (Obtained from http://www.periodic.lanl.

gov/mendeleev.htm)

The Pilgrimage

(Figure 3.2). Meaningful prediction becomes

the standard within the scientific method for

establishing meaningful understanding. Our

purpose here is not to elaborate on the scien-

tific method, but to demonstrate the scientific

method in action in the process of developing

and substantiating a new basis for the function

of biomolecular machines. As for the question

of Thales of Miletus, the fundamental answer is

that the world is made of more than 100 atomic

elements. Once the periodic law of the elements

was accurately established, it was determined

forever; it never has to be redone. The laws of

nature

are

constant.

Quite unlike the laws ema-

nating from our legislative bodies, once estab-

lished, the determined laws of nature provide

empowering understanding, but they remain so

only as long as the historical record remains

accessible.

For biology, the most common elements are

carbon

(C),

hydrogen

(H),

oxygen

(O),

nitrogen

(N),

and, to a more limited extent, sulfur (S).

These fighter atomic elements combine to form

the molecules of biology, including those of its

protein-based machines. Our task is to under-

stand how the molecules, especially the macro-

molecules of biology, function to sustain Life.

Before presenting an unfolding understanding

of biomolecular machines, however, the main-

stay of our pilgrimage recounts steps in the

development of our knowledge of the mole-

cules of biology.

3.1.4 Historical Proscription

There was a time, indeed quite recent in the

ascent of

man,"*

when products and components

Periodic Table of the Elements of Nature

Other metals

Rare earth

metals

Noble gases

Halogens

FIGURE

3.2. The Periodic Table of the Elements of

Nature. This table constitutes today's most complete

answer at the level of the elements, the atoms, to the

question posed by Thales of Miletus 26 centuries ago.

The spaces left by Mendeleev have been filled, and

many more elements have been added.

3.1 Initial Glimpses

of living organisms were considered beyond

man's competence to comprehend and beyond

man's potential to produce. This boundary

beyond which man's capacity was not to extend

prevailed long after the building of the great

gothic cathedrals. This barrier continued to

stand even after many of the profound advances

in science and medicine had withstood the test

of centuries—ev6n after the rousing advances

of Vesalius, Copernicus, Galileo, Harvey,

Malpighi, and Newton at renowned Universi-

ties like Padua, Bologna, and Cambridge.

In 1543, nearly three centuries before what

was to be the accidental rout of this particular

restraint to progress, two historic works were

pubUshed. In the first great book of modern

medical science, Humana Corpora Fabrica,

Vesalius ignored the constraints against human

dissection, accurately described human

anatomy, and thereby overturned 13 centuries

of Galenist dogma.^ In an antithetical view of

the cosmos entitled On the Revolutions of the

Celestial Spheres, Copernicus removed the

earth from the center of the universe.

Exactly two centuries before eventual bio-

logical enUghtenment, in 1628, Harvey^ pub-

Ushed De Motus

Cordis

showing the heart to be

not the seat of emotion but rather a mechani-

cal pump. Harvey further predicted the exis-

tence of capillaries to connect the outward flow

from the heart through the arteries to the

return flow through the veins, as subsequently

confirmed microscopically by Malpighi in

1661.

The Copernican view of the heavens had

been championed by Galileo, refined by

Kepler, and remarkably extended to a set of

axioms by Newton with the three laws of

mechanics, the resulting formulation of a uni-

versal law of gravitation, and the theory of the

tides.

Newton, who is viewed as the father of

modern physics, presented much of this in 1687

in his book

Principia,

often considered "one of

the most important works of science ever

written," thus capping the Scientific Revolution

of the seventeenth century.

Despite all this, more than another century

was yet to pass before a product or component

of a living organism was to be within man's

capacity to produce and to comprehend.

3.1.5 Accidental Synthesis

of Urea

The turning point, the first synthesis of a

product of living organisms, occurred in 1828

when Frederick Wohler,^ a chemist working in

Berlin, accidentally synthesized urea. Wohler

heated ammonium cyanate, NH4OCN, a well-

known inorganic compound comprised of

the NH/ and OCN~ ions. He recognized the

rearrangement product of heating as urea,

H2NCONH2, the natural non-ionic urinary

excretory product of mammals, now known to

be the primary nitrogen-containing product of

protein metabohsm.

This first organic^ synthesis began an extra-

ordinary Odyssey, emerging highUghts of

which continue to be greeted regularly with

excitement by the press, principally because

of their potential significance to health care,

to the economy, and to the environment.

This proscribed yet singular, accidental synthe-

sis of urea has transformed into the crescendo

that is the Biotechnological Revolution of

today.

Now man has the capacity to make, by chem-

ical synthesis at the laboratory bench, the major

products and components of living organisms.

Man has come to understand much of the

physical and chemical functioning of living

organisms. With this understanding, he can

design and prepare model proteins to emulate

the set of energy conversions that living organ-

isms require for survival. Furthermore, as a

hallmark of the Biotechnological Revolution,

man can transform living organisms into

chemical factories to work in society's

behalf,

for

example,

to produce natural as well as newly

designed products of use to society.

From the latter comes the fated promise to

replace the finite petroleum reserves and

to prepare products in an environmentally

friendly manner to sustain an increasingly

complex society. It is now possible, by genetic

engineering, to produce proteins that evolution

has never called upon nature to prepare and to

produce protein-based materials for addressing

primary problems required for sustaining our

society.

The Pilgrimage

3.1.6 Pasteur and Molecules with

Mirror Images

From within the reddish sediment of wine casks

and the genius of Pasteur began our under-

standing that carbon-containing molecules can

exist as mirror images, just as the left hand is

the mirror image of the right hand (see Figure

3.3). Pasteur found that the natural tartaric

acid^ molecule, from the red sediment of wine

ferment, rotated the plane of polarized light in

a rightward manner (dextro-rotatory), but that

L-amino acid residue

D-amino acid residue

FIGURE

3.3.

A Demonstration that the mirror image

converts a left hand into a right hand, but the hands

are otherwise identical. When a molecule has more

than one asymmetrical center, however, as occurs

commonly in carbon-containing molecules of

biology, for each asymmetrical center, x, there are

different structures as may be recognized by the

Fischer projection of glucose in Figure

3.4.

B The

two

optical (mirror image) isomers of the tetrahedral

carbon atom of amino acid residues, designated as an

L-amino acid residue on the left (the one that occurs

in biology's genetically produced protein) and as a

D-amino acid residue on the right (an optical isomer

that does occur in biology, but in those peptides not

encoded for by the genetic code). C The effect of

insertion of a D-amino acid residue in an otherwise

L-amino acid residue protein in the p-spiral structure

of the elastic-contractile model protein of our focus

would be to disrupt the regular structure. This is

dif-

ficult to avoid completely in chemical synthesis, and

it increases the temperature at which occurs the

inverse temperature transition and decreases the

heat of the transition due to less optimal association

of oil-like groupings.