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."

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