Researchers at Canada's National Institute for Nanotechnology (NINT) are learning which molecular scale factors affect the assembly and disassembly of microtubules that are part of a cell's skeleton. Microtubules control the division of all cells with a nucleus by constantly assembling at one end while they disassemble at the other. Failure in either of these processes can lead to abnormal cell division causing improper development of an organism, incomplete differentiation of a tissue, or uncontrolled cell division, as in cancer.

The research of Andriy Kovalenko, Leader of NINT's Theory and Modeling Group, uses modern theoretical and modeling approaches to get new insight into which forces between the molecular constituents are critical for that correct assembly of the molecules of tubulin in the microtubles. This work applies a new molecular theory of solvation, developed by Andriy Kovalenko and collaborators, to predict which forces drive the self-assembly of proteins into macromolecular structures, such as the microtubules. This prediction has not been possible with conventional simulation approaches because of the size and complexity of the system involved.

Conformation and arrangement of two adjacent tubulin dimers in protofilaments forming a periodic two-dimensional sheet in aqueous solution. Vertical white lines denote the protofilaments axes. Molecular dynamics simulations are used to optimize the tubulin conformations and arrangement in protofilaments, and subsequently, employ three-dimensional molecular theory of solvation (aka 3D-RISM) to predict the hydration structure of protofilaments and the solvent-mediated effective potential between them. (Image courtesy of National Institute For Nanotechnology / National Research Council Of Canada)

In their most recent paper, published as the cover story in the January 15, 2007 edition of the Biophysical Journal, Kovalenko and his colleagues at NINT and the Unversity of Alberta have identified that the interaction between the long filaments that form the microtubular structure is most strongly affected by the conformation of the M-loop, a small segment of the protein chain located on one side of the tubulin monomer. They also determined the relative balance in these interactions between the energy of attraction or repulsion and the disorder (entropy) imposed by the interaction with the solvent. This is possible because the theory explicitly accounts for both the proteins and the solvents and counter ions in the system.

Identification of the M-loop as the principal component of tubulin responsible for affecting the assembly of the filaments, as compared to the sequence of tubulin, is an important new insight that could lead to new approaches for rational drug design and to focus experimental and theoretical efforts in the study of microtubules and their function.