Putting randomness to work: unique form of nanoscale random motion may drive key cellular functions

June 03, 2001

New research into the activity of a key "motor" protein suggests that a unique form of random motion powered by thermal energy may play a vital role in moving enzymes and other chemicals inside cells. Beyond providing a better understanding of sub-cellular functions, the National Science Foundation-sponsored work may offer a new mechanism for generating motion in future nanometer-scale machines.

Within the cells of the body, kinesin proteins work like "cellular tow trucks" to pull tiny sacks of chemicals along pathways known as microtubules. The accepted explanation for this motion is that the kinesins use their two leg-like "heads" to walk along the microtubule paths in a deliberate way, fueled by the energy molecule adenosine triphosphate (ATP).

But in a paper published in May issue of the journal Physical Review E, Georgia Institute of Technology physicist Ronald Fox argues that what appears to be a walk along the microtubule is really random motion cleverly constrained by chemical switching carried out by ATP.

"These are certainly not motors in the sense of burning a fuel and having a concerted effort in a one-directional way," said Fox. "If you could see them, their walk would appear to be more like a drunken sailor than a concerted motion."

Composed of fibrous proteins, the microtubules include sites approximately 8 nanometers apart where kinesin heads can bind chemically. To move along this pathway, Fox argues that the kinesins use "rectified Brownian motion" in the following steps: "Normally, Brownian motion cannot do anything concerted or with directionality, because it is random," Fox explained. "But what happens here is a random process in a system that has asymmetric boundary conditions created by the ATP switching. That makes it possible to get a net directed motion along the microtubule."

The model described by Fox and post-doctoral colleague Mee Hyang Choi depends on two unique properties of structures at the nanometer-scale: thermal energy can be a robust source of power, and random motion occurs very rapidly.

"Normally, we would think of Brownian motion - or diffusion - as a very slow process," he noted. "But when you are on the nanometer scale, Brownian motion is a very rapid way to do things. Even though it is random, it allows you to explore all the possibilities very rapidly."

Using optical tweezers and other sophisticated techniques, biologists have studied the activity of kinesins, measuring their speed, pulling power and use of ATP. For instance, they can move at velocities of up to 1,000 nanometers a second, and exert forces of as much as 6 piconewtons.

Richard Fishel, professor of microbiology and immunology at the Kimmel Cancer Institute in Philadelphia, Pa., studies how DNA repair genes locate and bind with damaged DNA. He believes all nucleotide-dependent processes really involve a switching mechanism, and says Fox's model explains how that works for a broad range of systems in the context of thermally powered Brownian motion.

"Ron Fox has now set the clear physical dimensions for how that has to work, and how it has to work is by rectified Brownian motion," he said. "The rectification of those Brownian events is done by the small molecule exchange of ATP for ADP. The energy that drives that process is what's important."

The switching operation that involves acceptance or removal of a phosphate controls a protein's affinity for binding to other proteins it encounters as Brownian motion moves it through cells. "What Ron has provided here is the physical reasoning behind how these collisions can work and the conformational transitions that are rectified," he explained.

The role of Brownian motion in cellular activity has been discussed before, but new experimental results and high-level mathematics in Fox's model provide the strongest evidence yet to support it. Though the experimental results are consistent with the model of rectified Brownian motion, Fox admits there is no indisputable evidence supporting his model over the accepted "power stroke" theory.

"What we really need now is an experiment that will clearly be consistent with one of these mechanisms and not the other," he noted. "That's our objective for the immediate future."

Fishel argues that a paper published May 24 in the journal Nature by researchers at the University of Tokyo and the University of California supports Fox's model of ATP switching.

Beyond the biological implications, Fox hopes the paper leads nanotechnology researchers to think about heat and motion in a new way.

"There are lessons here for nanotechnology in these biological nano-systems," he added. "This will help people to appreciate that thermal motion can actually be harnessed to do many kinds of useful work."

And the work may also restore the original hypothesis of Robert Brown, who first observed the phenomena bearing his name in pollen particles moving through water. Brown first believed that what we saw through his primitive microscope was "the secret of life." But after observing the same kind of motion with inorganic particles, he discarded that belief with disappointment.

"We're arguing that Brown really had discovered the secret of life," said Fox. "When you get into this sub-cellular level on the nanometer scale, the dynamics and vitality of protein molecules is really due to thermal motion."
-end-
The research was sponsored by the National Science Foundation.

Research News & Publications Office
Georgia Institute of Technology
430 Tenth Street, N.W., Suite N-116
Atlanta, Georgia 30318 USA Media Relations Contacts: John Toon (404-894-6986); E-mail: (john.toon@edi.gatech.edu); Fax: (404-894-4545) or Jane Sanders (404- 894-2214); E-mail: (jane.sanders@edi.gatech.edu); Fax: (404-894-6983).

Technical Contacts: Ron Fox, Georgia Institute of Technology (404-894-5260); E-mail: (ron.fox@physics.gatech.edu) or Richard Fishel, Kimmel Cancer Institute (215-503-1345); E-mail: (rfishel@hendrix.jci.tju.edu).

Georgia Institute of Technology

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