Microtubule Stability Studied by Three-dimensional Molecular Theory of Solvation

¹ National Institute for Nanotechnology

^* To whom correspondence should be addressed. E-mail: andriy.kovalenko{at}nrc-cnrc.gc.ca.

Submitted on May 24, 2006
Revised on June 29, 2006
Accepted on 28 September 2006

	Abstract

We study microtubular supramolecular architectures of tubulin dimers self-assembling into linear protofilaments, in turn forming a closed tube which is an important component of cytoskeleton. We identify the protofilaments arrangements with the lowest free energy by using molecular dynamics to optimize tubulin conformations, and subsequently, the three-dimensional molecular theory of solvation (3D-RISM) to obtain the hydration structure of protofilaments built of optimized tubulins and the solvent-mediated effective potential between them. The latter theoretical method based on first principles of statistical mechanics is capable of predicting the structure and thermodynamics of solvation of supramolecular architectures. We obtained a set of profiles of the potential of mean force between protofilaments in a periodic two-dimensional sheet in aqueous solution. The profiles were calculated for a number of amino acid sequences, tubulin conformations, and spatial arrangements of protofilaments. The results indicate that the effective interaction between protofilaments in aqueous solution little depends on the isotypes studied; however, it strongly depends on the M loop conformation of -tubulin. Based on the analysis of the potential of mean force between adjacent protofilaments, we found the optimal arrangement of protofilaments which is in good agreement with other studies. We also decomposed the potential of mean force into the energetic and entropic components, and found that they both are considerable in the free energy balance for the stabilized protofilaments arrangements.

Key Words: microtubules, potential of mean force, solvation, supramolecular architecture, three-dimensional reference interaction site model (3D-RISM), tubulin

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