The Virginia Tech College of Science’s Shengfeng Cheng has won a seed grant of $100,000 from the Jeffress Memorial Trust to create an intricate computer model of how tubulin proteins connect to one another to form microtubules, the scaffolding on which cells are built.
Cheng, an assistant professor with the Department of Physics, likens tubulin proteins to bricks that can be assembled into a wide variety of superstructures. One key difference: Building bricks stay immobile once in mortar. Tubulin proteins on the other hand are spontaneous as they move, self-assemble, deform, and detach, thus causing the hollow-tubed microtubules they form to grow and shrink.
The capability of switching between the growth and shrinkage, which is termed “dynamic instability”, allows complex microtubule networks to extend and remodel throughout the gel-like interior of a cell. This dynamic nature of microtubules is vital to cell functions, including cell division.
However, the process of how tubulin proteins form helical-shaped microtubules is not well understood. The exact pattern the proteins take in microtubules is still debated: Are they striped like a barber’s pole or more alternating like a chess board? What is the instigator of the growth and shrinkage process?
Cheng says if this dynamic instability in cells could be understood, it could not only lead scientists to discover a crucial secret behind the cell’s ability to perform so many different functions, but also point to new ways to control the process. If the growing and shrinking of microtubules can be, as Cheng puts it, “placed in a timeout,” cells could be halted from dividing.
The implication is huge: If cancer cells can be halted from dividing from the inside, doctors could help slow or altogether stop its spread.
“This is the reason that many potential cancer drugs are designed and being developed to interfere with this process so cancer cells can be killed,” added Cheng. “However, we still lack a good understanding of the self-assembly mechanism of microtubules.”
Working on Cheng’s team are Chola Regmi, a postdoctoral associate; junior Christopher Dobson of Virginia Beach, and senior Ryan Grosenick of Midlothian, Virginia, all in the Department of Physics.
The group will build the computational model of tubulin proteins with assistance from a supercomputer known as IMAGINE, located at the Virginia Tech Corporate Research Center. The high-performance computer is partly supported by Virginia Tech’s Institute for Critical Technology and Applied Science.
IMAGINE is short for Innovative Materials discovery Accelerated through a Genomics and INformatics Engine. It has been in use by Cheng’s group since spring 2014 for several projects that emphasize a genomic approach toward next-generation materials. IMAGINE is equipped with state-of-the-art graphic processing computational nodes, enabling fast and large-scale molecular simulations that are needed to deal with large protein complexes such as microtubules.
In the model, Cheng says the nanometer-sized cell proteins will be represented as a “nanoparticle” made of beads connected by springs, with the nanoparticle having the capability to self-assemble into microtubules when many of them are placed in a “simulation” box. The box being a “cell.”
“With this model, we will investigate the self-assembly process of microtubules, understand how the structure is controlled, and study the dynamic nature and mechanical properties of microtubules,” added Cheng, who says his approach is unique because he and his team are looking at the tubulin proteins in cells as bricks in, say, a church, that is not a biological standing, but a more cold architectural standpoint. Except this church can morph and subdivide at will.
But how those bricks form that original church, or tubulin proteins form a microtubule, is the first part of the whole mystery, said Cheng, an affiliated member of Virginia Tech’s Macromolecules and Interfaces Institute.
“Specific unanswered questions include: Why are microtubules helical? Why is a certain kind of tubes predominantly produced over other possible structures? Why can microtubules switch between a growth and a shrinkage phase intermittently and how? What features of protein‐protein interactions are responsible for the nontrivial mechanical properties of microtubules?” said Cheng, who hopes to use the $100,000 award and any resulting early work to spur future grants from external funding agencies.
Part of the nonprofit Health Resources in Action, the Jeffress Trust Awards Program provides support for one-year pilot studies that encourage the development of innovative interdisciplinary strategies that integrate computational and quantitative scientific methodologies across a broad range of scientific disciplines.