Volume 3, Issue 21 June 2006
Start Your Protein Engines
George Oster is also a professor with the College of Natural Resources' Department of Environmental Science, Policy & Management.
In the world of hot rods, UC Berkeley professor George Oster would be considered a "motorhead." He knows the ins-and-outs of motor mechanics, from stroke cycles and rotary processes to thermodynamics and fuel efficiencies. But the motors he studies aren't new souped-up engines built for today's automobiles. Oster, a professor of cell and developmental biology, examines the biological nanomachines that propel bacteria through our world and pack DNA into viruses against incredible pressures.
Oster and his research group investigate the physics and chemistry behind great engineering mysteries of the natural world, from protein motors to cell motility to how bacteria form thriving populations that aren't so different from ant colonies, or even human societies.
"It's like figuring out how people walk and then putting them in a football stadium to see how they behave in a crowd," says Oster, also a faculty affiliate in the California Institute for Quantitative Biomedical Research (QB3) and a professor of mathematical ecology. "But we always start with the physics, like how do they move in the first place?"
For several years, Oster has addressed fundamental questions about protein motors, identifying their energy sources and uncovering how that energy is converted into mechanical forces.
"We have to combine structural biology, biochemistry, thermodynamics, mutation studies, and other lines of inquiry and then synthesize all of it into a mathematical model," Oster says. "That model has to both fit with existing experiments and also suggest new experiments to do."
A computer-generated model of the structure of ATP synthase, including the two motors (marked here as F0 and F1).
For example, in recent years Oster and his colleagues created a groundbreaking model of ATP synthase, an enzyme that synthesizes ATP, the universal fuel molecule that powers all cells. ATP synthase is essentially a factory built around two rotary motors. One of the motors forces the other to rotate as a generator that cranks out ATP. Oster's contribution was in showing how the two motors generate their torque from very different fuel sources.
The first motor is essentially electric. It's powered, Oster explains, by a transmembrane electro-chemical potential that drives the flow of ions across the cellular membrane. The other motor is powered by ATP, the same substance that the enzyme produces.
Of course, ATP synthase is only one of nature's many protein motor systems. Working with UC Berkeley professor Carlos Bustamante, researchers have also studied the motor that packs a virus's DNA so tightly that it can be injected into a hijacked cell at ten times the pressure of a cork shooting out of a champagne bottle. And they've modeled the donut-shaped molecular motors that move along DNA strands during replication.
The biomolecular portal motor of bacteriophage PHI-29 (yellow) compresses the coiled DNA into the viral capsid at 6,000 times its normal pressure. (courtesy the Bustamante group)
"The cylinders all operate in sequence like an old-fashioned airplane motor," Oster says.
As the researchers better understand how, say, bacteria propel themselves, they're also investigating where the organisms' motility takes them. When hundreds of thousands gather together, Oster says, they can signal each other to "self-organize into elaborate structures that are symmetrical and beautiful," while also serving a biological purpose. But what are those rules of higher-level organization? And what might they tell us about higher-level organisms that coordinate their own collective activities?
It's these kinds of nested puzzles that keep Oster fascinated, he says.
"No model is final and all models are wrong in some detail or other," he says. "So we're always revisiting old models and patching them up or throwing them out and making new ones. You don't want to get too attached to your models."
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The New New Math of String Theory
Earlier this year, Mina Aganagic co-organized a Mathematical Sciences Research Institute (MSRI) program on New Topological Structures in Physics to encourage collaborations between mathematicians and physicists working on problems such as String Theory.
At the beginning of the last century, Albert Einstein posited a now famous theory that forever linked geometry and fundamental physics. According to general relativity, spacetime is curved, and that curvature affects the behavior of matter, and vice versa. However, Einstein couldn't contend with quantum mechanics. At that small scale, classical geometry—the stuff we all learn in elementary school—breaks down. What replaces it? Mathematical physicists, like UC Berkeley professor Mina Aganagic, are still figuring that out.
"The basic question is what does geometry look like at very short distances?" says Aganagic, who holds a joint appointment in the Department of Physics and Department of Mathematics.
The distances that Aganagic delves into are on order of the Planck scale, 10 to the minus 33 centimeters, the smallest unit of space in our universe. That's where classical geometry, which goes hand-in-hand with classical physics, fails us and the spectacular idea of string theory emerges.
String theory attempts to unite Einstein's general theory of relativity and quantum mechanics under one umbrella, or "theory of everything," that explains all of the fundamental forces and particles in our universe. According to string theory, all elementary particles are tiny vibrating strands of energy. In mathematical terms, points, which are elementary objects in classical geometry, aren't really point-like at all.
"String theory is the only known solution to the problem which is at the core of modern physics: the incompatibility of quantum mechanics and gravity," says Aganagic.
"If you could look at them from far away, they'd look like points," Aganagic says. "But if you get close enough, you'd realize that they're really one-dimensional loops."
Unlike the three-dimensional world that we perceive, these loops of string vibrate in ten dimensions. Every kind of particle and force corresponds to the particular vibrational pattern of a string. While there is no experimental proof yet that string theory is correct, Aganagic says that putting the physics through the mathematical ringer is not entirely unlike experimental verification.
"You could say that what we're discovering is quantum geometry," she adds.
For example, one problem she has investigated involves calculating the entropy of black holes. According to classical physics, material that falls into a black hole could vanish from our universe entirely, violating the Second Law of Thermodynamics. However, string theory provides a "fantastically clever way of solving the problem," Aganagic says, without violating any fundamental laws of nature.
"Unlike in Einstein's time when the relevant mathematics was already in existence, the mathematics we need now hasn't been fully developed yet,& Aganagic says. "This time around, math and physics are being discovered in parallel."
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Molecular Rules Of Engagement
Phil Geissler is a fellow of the David and Lucile Packard Foundation and of the Alfred P. Sloan Foundation.
A single molecule doesn't usually do much of anything. But combine a large number of molecules together and various sorts of amazing things can happen. Networks of polymers interact to propel cells, molecules in a plant's leaf work together to convert sunlight into energy, and so on. But what are the rules that give rise to these emergent behaviors and can we control them? UC Berkeley scientist Phil Geissler is using the tools of theoretical chemistry to find out.
"What intrigues us in a very generic sense is how molecules can act in concert to give rise to behavior that is unexpected on scales that are relevant for things like biology and materials science," says Geissler, a professor in the Department of Chemistry and a faculty affiliate in the California Institute for Quantitative Biomedical Research (QB3).
In each research effort, Geissler and his colleagues construct simple models to gain insight into how molecules may interact. For example, they might start with a group of molecules at equilibrium and then attempt to discern and predict what will happen when that system is disturbed by adding, say, light, or triggering a chemical reaction. The goal is not to create a highly-detailed model, but rather one that "has just enough meat on it" to be valuable, Geissler says. Simplified models, he explains, allow both thorough statistical analysis and a clear way to discern the effects of specific physical ingredients.
"The tools we use are pencil and paper and some computer simulation," says Geissler, who recently earned a prestigious Sloan Foundation Research Fellowship. "I haven't gotten my hands wet in a long time."
An illustration of the models of biological polymers that Geissler's group is studying in connection with Dan Fletcher's experiments on actin networks. Each line represents an actin filament. The color and width of a segment indicate its strain during a typical equilibrium fluctuation. (Red and thick means more highly distorted, thin and blue means more weakly distorted.) This configuration demonstrates the emergence of force patterns that result from connections between different molecules. (courtesy the researchers)
Instead, Geissler is collaborating with UC Berkeley experimental nanoscientists Dan Fletcher, Matthew Francis, and Paul Alivisatos, to apply his models to the nanoscale realm of self-assembly. In recent years, synthetic chemists and biologists have identified or created a wide array of organic and inorganic materials with fascinating electronic and optical properties. Some of these materials could perhaps lead to the likes of nanoscale computers that are extraordinarily faster than today's processors, or solar cells far more efficient than state-of-the-art photovoltaics. The challenge though is arranging these tiny components into precise patterns that can be wired together into a useful system.
"It sounds like a pipe dream," Geissler says, "but we're exploring ways to alter the conditions in which these simple components live so that they self-assemble into interesting structures."
In recent work, Geissler and Fletcher have investigated how rather stiff biological polymers can induce motion within a cell. Consisting of proteins such as actin, these filaments provide the cell's structure and mechanical integrity but also work together to power a cell's forward motion.
"You'd think that if you could figure out how one filament works, you could jump to understanding the entire network," Geissler says. "But that's not the case. So we're involved in developing models that describe how these filaments talk to one another in a network and the consequences of that communication and cooperation."
Results of a computer simulation for a system of "light harvesting complexes," in this case the protein shells of viruses, whose interactions can be turned on and off. From these simulations, Geissler and Matt Francis hope to learn how varying the strength, variety, and time-dependence of interactions leads to controllable capsid arrangements. Eventually, they aim to mimic this behavior in a bio-artificial solar cell.
Based on such models, Geissler and Fletcher are now considering whether they can take inspiration from the motion of chloroplasts, responsible for the energy conversion within plant cells, to build bio-artificial solar cells. One reason plant cells are so efficient at converting sunlight into energy, Geissler explains, is because they can modulate how much light is absorbed. That's possible because the chloroplasts can move to and away from the light as necessary to achieve maximum efficiency and avoid damage from too much light. The researchers hope to eventually incorporate that into a synthetic solar cell inspired by nature's emergent behavior.
"It's all a matter of figuring out how to program complex, rational behavior into systems that live by simple rules."
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