DYNAMIC INSTABILITY OF MICROTUBULES - MONTE-CARLO SIMULATION AND APPLICATION TO DIFFERENT TYPES OF MICROTUBULE LATTICE

Dynamic instability is the term used to describe the transition of an individual microtubule, apparently at random, between extended periods of slow growth and brief periods of rapid shortening. The typical saw tooth growth and shortening transition behavior has been successfully simulated numerically for the 13-protofilament microtubule A-lattice b y a lateral cap model (Bayley, P. M., M. J. Schilstra, and S. R. Marti n. 1990. J Cell Sci. 95:33-48). This kinetic model is now extended sys tematically to other related lattice geometries, namely the 13-protofi lament B-lattice and the 14-protofilament A-lattice, which contain str uctural ''seams.'' The treatment requires the assignment of the free e nergies of specific protein-protein interactions in terms of the basic microtubule lattice. It is seen that dynamic instability is not restr icted to the helically symmetric 13-protofilament A-lattice but is pot entially a feature of all A- and B-lattices, irrespective of protofila ment number. The advantages of this general energetic approach are tha t it allows a consistent treatment to be made for both ends of any mic rotubule lattice. Important features are the predominance of longitudi nal interactions between tubulin molecules within the same protofilame nt and the implication of a relatively favorable interaction of tubuli n-GDP with the growing microtubule end. For the three lattices specifi cally considered, the treatment predicts the dependence of the transit ion behavior upon tubulin concentration as a cooperative process, in g ood agreement with recent experimental observations. The model rationa lizes the dynamic properties in terms of a metastable microtubule latt ice of tubulin-GDP, stabilized by the kinetic process of tubulin-GTP a ddition. It provides a quantitative basis for the consideration of in vitro microtubule behavior under both steady-state and non-steady-stat e conditions, for comparison with experimental data on the dilution-in duced disassembly of microtubules. Similarly, the effects of small tub ulin-binding molecules such as GDP and nonhydrolyzable GTP analogues a re readily treated. An extension of the model allows a detailed quanti tative examination of possible modes of substoichiometric action of a number of antimitotic drugs relevant to cancer chemotherapy.