Biophys J, August 2002, p. 663-680, Vol. 83, No. 2

Relating Molecular Flexibility to Function: A Case Study of Tubulin

Ozlem Keskin,^* Stewart R. Durell, Ivet Bahar,^§ Robert L. Jernigan, and David G. Covell^*

 ^*Computational Technologies Laboratory, Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702 USA;  College of Arts and Sciences, Department of Chemistry, Koc University, Rumelifeneri Yolu, 80910 Sariyer, Istanbul, Turkey;  Molecular Structure Section, Laboratory of Experimental and Computational Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 USA; and  ^§Center for Computational Biology and Bioinformatics, and Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 USA

Microtubules (MT), along with a variety of associated motor proteins, are involved in a range of cellular functions including vesicle movement, chromosome segregation, and cell motility. MTs are assemblies of heterodimeric proteins, -tubulins, the structure of which has been determined by electron crystallography of zinc-induced, pacilitaxel-stabilized tubulin sheets. These data provide a basis for examining relationships between structural features and protein function. Here, we study the fluctuation dynamics of the tubulin dimer with the aim of elucidating its functional motions relevant to substrate binding, polymerization/depolymerization and MT assembly. A coarse-grained model, harmonically constrained according to the crystal structure, is used to explore the global dynamics of the dimer. Our results identify six regions of collective motion, comprised of structurally close but discontinuous sequence fragments, observed only in the dimeric form, dimerization being a prerequisite for domain identification. Boundaries between regions of collective motions appear to act as linkages, found primarily within secondary-structure elements that lack sequence conservation, but are located at minima in the fluctuation curve, at positions of hydrophobic residues. Residue fluctuations within these domains identify the most mobile regions as loops involved in recognition of the adjacent regions. The least mobile regions are associated with nucleotide binding sites where lethal mutations occur. The functional coupling of motions between and within regions identifies three global motions: torsional and wobbling movements, en bloc, between the - and -tubulin monomers, and stretching longitudinally. Further analysis finds the antitumor drug pacilitaxel (TaxotereR) to reduce flexibility in the M loop of the -tubulin monomer; an effect that may contribute to tightening lateral interactions between protofilaments assembled into MTs. Our analysis provides insights into relationships between intramolecular tubulin movements of MT organization and function.

Biophys J, August 2002, p. 663-680, Vol. 83, No. 2
© 2002 by the Biophysical Society   0006-3495/02/08/663/18  $2.00

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