Hitching a ride on the kinesin train

Top: Electrostatic properties of the kinesin family. Electrostatic properties of different kinesin representatives are expressed as a color spectrum ranging from positive (blue) to negative (red).

 

Middle: A consensus electrostatic potential map of the kinesin family illustrating conserved charged regions. Note the consistent positive blue patch on the rear face of the protein which binds microtubules.

 

Bottom: Electrostatic clustering of available kinesin structures groups functionally similar proteins. See PLoS research article for more details.

 

Images courtesy of Barry J. Grant, University of Michigan.

Kinesin is the molecular "locomotive" that travels along the microtubule "train tracks" of our brains. When malfunctions bring them to a stop, diseases like Alzheimers result; for that alone the molecule would be an intriguing object of study. But kinesin's signifance to the field of nanotechnology may be even more profound.

Researchers at the University of California, San Diego, in collaboration with several universities in the US, United Kingdom, and Poland, have developed a new picture of how kinesin molecules move along microtubules - and how diseases bring them to a halt.

The new findings, published in the November 2011 issue of the journal Public Library of Science - Biology, are also significant in that they indicacted that kinesin plays a critical role in moving the chromosomes apart during cell division. Indeed, a number of the most important existing cancer drugs, such as taxanes and vinca alkaloids, work by targeting these transport systems in rapidly dividing cancer cells.

Kinesins are a family of microtubule motor proteins active in mitosis, or cell division. These kinesins use chemical energy from the hydrolysis of ATP (adenosine triphosphatase), a compound that the body produces from food to generate energy as needed by the body.

Using the Triton Resource, a medium-scale high performance computing system at UC San Diego’s San Diego Supercomputer Center, researchers developed computational simulations of kinesin ‘engines’ hauling cargo along microtubule rails within cells. The findings show that electrostatic attraction between the engine and the rail is critically important in making the railway work. Videos showing the simulations can be viewed via the following links:

• Kinesin electrostatics
• Electrostatic conservation within the kinesin family
• Surface mapped electrostatic potentials of the kinesin family

“Precisely how kinesin motor proteins move along their microtubule tracks is an important question in biology,” said J. Andrew McCammon, a theoretical chemist and pharmacology researcher at UC San Diego and the Howard Hughes Medical Institute; McCammon was also the senior author of the research paper, Electrostatically Biased Binding of Kinesin to Microtubules.

“We know that some kinesins have twin ‘heads’ that alternately bind to and step along microtubules in a coordinated walking action. But more usually, kinesins have only one head, and how single-headed kinesins produce force and movement is poorly understood,” McCammon said.

In the study, researchers addressed this question and concluded that electrical attraction between single kinesin heads and microtubules is a critical factor deciding the direction of movement: each time the head approaches a microtubule, it slides forward by the electrical attraction between the engine and the track.

Implications for Nanoengineering

“This research shows that computational methods can be used to rationally design mutant molecular motors, with altered electrostatic properties, that can regulate the speed of the railway,” said Barry Grant, a researcher at the University of Michigan at Ann Arbor and former member of McCammon’s research lab at UC San Diego.

In keeping with the train analogy, speeding up means having a more efficient transport of cargo, perhaps by means of a drug. Slowing the speed provides researchers with a good test of the general operational constraints for producing directed motion on the molecular scale, which is informative for future nanoengineering projects. Moreover, defects in motor-dependent processes, such as slowing down or stopping altogether, are associated with a large range of diseases, including neurodegeneration, tumorigenesis, and developmental defects.

“Some of these calculations for these protein simulations required quite a large amount of computer memory, so the Triton Resource proved to be very helpful in this work,” Grant said, noting that each simulation in the project consumed about seven gigabytes of RAM per core with subsequent analysis of data sets measuring almost two terabytes in size. A single terabyte is one trillion bytes of data, about equal to the information printed on paper made from 50,000 trees.

Said McCammon, “Ultimately, construction of molecular motors to arbitrary specifications will provide a powerful toolkit for therapeutic delivery and nanotechnology applications.”

A version of this article first appeared on the SDSC website.