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News from ICTP 97 - Features - Protein Folding
An ICTP workshop on protein folding brought together biologists and physicists to discuss one of the most prominent issues in medical science and public health today.
Proteins, Foldings and Physics
Often the most fundamental questions
are the most difficult to answer.
When you think about it, all living organisms, despite their endless
complexity, are able to put themselves together without any outside
help or direction. They have accomplished this task over eons
of time through a process of self-replication that has defied
scientific understanding.
How does an embryo evolve into a fetus and then into an infant?
How are chemical and biological elements transformed into molecules
and then into cells--and how are cells ultimately transformed
into blood vessels, muscles, organs and bones? How do the physical
and biological factors that distinguish one species from another--yet
that make all organisms within the same species very much alike--reveal
themselves time and again from one generation to the next?
All fundamental questions. All difficult to answer.
The 50,000 plus proteins found in human beings, each one with
its own unique function and shape, constitute the building blocks
of life. They are responsible for everything from haemoglobin
that carries oxygen in our blood, to antibodies that fight infection,
to insulin that allows us to convert sugar into energy, to actin
and myosin that enable muscles to expand and contract.
Organically, proteins are molecules or chemical compounds. Physically,
they may first appear as beaded strings but they quickly (in fact
almost spontaneously) transform themselves into compact three-dimensional
structures.
A protein's function, its very reason for existence, is determined
by its shape in one of nature's most magnificent displays of how
form can dictate function. The road to this discovery began some
50 years ago when the great 20th century chemist, Nobel Laureate
Linus Pauling, detected that two simple arrangements of proteins--a-helix
and b-sheet--are found in virtually all proteins.
Protein folding--its transformation from a beaded string into
a compact structure--takes place spontaneously. That much we know.
Ever since Pauling's discovery, however, scientists have been
trying to determine what biological and chemical factors drive
the folding of proteins and, equally important, how proteins inherently
self-replicate themselves into the appropriate shape time and
again given the endless possibilities that are available.
This research effort has spurred a great deal of progress in our
understanding of protein structure and behaviour. It has also
generated a great deal of data. Yet, the protein folding problem,
as scientists have come to call it, remains one of the great unanswered
questions in science--the biologists' equivalent to the physicists'
inability to unify gravity with nature's other elementary forces.
Until recently, this problem resided within the exclusive intellectual
domain of biologists and chemists. Now, physicists, in another
example of the increasing blurring of boundaries between disciplines,
have begun to examine the problem using analytical tools usually
associated with their discipline--theories related to thermodynamics
and complex systems. The result has been a cross-fertilisation
of ideas and techniques that have enriched both biology and physics
and hinted at intriguing strategies for answering this perplexing
question.
ICTP's Workshop on Protein Folding Structure and Design, held
between 11-22 June 2001, was designed to foster discussion among
biologists and physicists working on issues related to the protein
folding problem. Some 40 scientists, divided equally among the
two disciplines, were in attendance.
Workshop participant Arthur Lesk, a molecular biologist at the
University of Cambridge (UK) and author of Introduction to
Protein Architecture (Oxford University Press, 2001), makes
the case for this marriage of disciplines by noting that "physicists
are good at creating simplified computational models that show
essential characteristics of real-world systems. Biologists, meanwhile,
have acquired a vast storehouse of knowledge and understanding
by carefully examining the real-life behaviour of these systems.
By working together, we might be able to accelerate our research
efforts ultimately providing important insights that help to explain
the protein folding process."
Jayanth R. Banavar, a workshop organiser and physicist at Pennsylvania
State University (USA), adds that the time is right for such a
union of knowledge and skills.
"First," he notes, "there has been an explosion
of data related to genes and proteins largely due to the monumental
work associated with the Human Genome Project. But deciphering
the sequence of genes--that is, pinpointing the genes' location
on the DNA string--while an extraordinary feat, is only the beginning.
The ultimate goal is to understand how proteins function--and
that can only be accomplished by understanding protein folding."
"Second," Banavar notes, "the past decade has experienced
a never-ending explosion in computer power that now allows scientists,
particularly physicists and mathematicians whose training is well-grounded
in these areas, to approximate the real-world behaviour of complex
systems with greater and greater accuracy."
"Third, these new tools have been put to use in a variety
of fields, including studies of ecosystems, climate change and
stock market behaviour, that have enabled the physics and mathematics
communities to enter into partnership with other disciplines in
ways that were not even considered possible-or for that matter,
interesting--a decade ago."
"And fourth, protein-folding research could have direct implications
for public health." That's because protein folding--or, more
precisely, protein misfolding--has been implicated in the rising
incidence of some disturbing and deadly diseases, including Alzheimers'
disease, mad cow disease and even some forms of cancer.
"Protein folding is a remarkable process not only for its
precision but for its reproducibility," says Amos Maritan,
who holds a joint appointment at the International School for
Advanced Studies (SISSA, Trieste, Italy) and ICTP. Maritan, with
his colleague Banavar, served as a local organiser of the workshop.
"Yet the folding process sometimes goes awry and increasingly
scientists are coming to believe that when such misfolding occurs
it can have dire health-related consequences."
Here's why. Proteins consist of a greasy core of 'hydrophobic'
aminoacids surrounded by an outer coating of 'hydrophilic' aminoacids.
When proteins misfold, for reasons that cannot yet be explained,
the greasy centre leaks through the watery coating to leave behind
a pasty material--sometimes referred to as plaque or even less
generously as gunk. This unwanted material can eventually create
a mass of sticky fibers that cause an increasing number of proteins
to lose their natural structure and thus their normal function.
Scientists are coming to believe that the unwelcome cumulative
result of this process, which is driven by a complex array of
biological, chemical and physical factors, may be responsible
for such diseases as Alzheimer's and Creutzfeld-Jacob's (commonly
called mad cow disease).
As a result, a better understanding of how proteins fold and misfold
could set the stage for devising therapies for the treatment of
these deadly diseases.
Such understanding will take time, as will efforts to design protein-based
drugs targeted for specific protein structures deemed responsible
for the ailments. For now, activities such as the ICTP Workshop
on Protein Folding, Structure and Design offer an opportunity
for biologists and physicists to learn more about each other's
work in ways that will both strengthen and expand the foundation
of basic science underlying this broad-ranging interdisciplinary
initiative.
"At the turn of the 20th century," notes Maritan, "scientists
had acquired a great deal of information about atoms but no unifying
framework was in place to understand their general structure and
behaviour. That unifying framework, which although impressive
remains incomplete, was built by a group of theoretical physicists
working hand-in-hand with their experimental counterparts. Perhaps
we are in the same position today when it comes to questions of
protein folding: Physicists working with biologists, chemists
and other researchers may together synthesise the enormous amount
of data, information and insight we have accumulated over the
past half century to help unlock one of the great mysteries that
has impeded understanding organic structures and protein behaviour."