Non-equilibrium tubulin conformational transitions drive microtubule dynamic instability

Dynamic instability underlies all microtubule functions, yet its mechanism has remained elusive since its discovery in 1984 due to limitations of the classical GTP-cap model. We present a first-principles mechano-chemical model in which dynamic instability emerges from non-equilibrium transitions among bent (B), straight (S), and curved (C) conformations of tubulins and their longitudinal interfaces within the microtubule lattice. Growth, shortening, catastrophe, rescue, and pausing are each controlled by distinct kinetic pathways and energy landscapes for B→S and S→C transitions. The inherent polarity of the microtubule lattice imposes asymmetric pathways, giving rise to distinct dynamic behaviors at the minus-end. This model not only resolves long-standing conceptual puzzles but also quantitatively reproduces the full spectrum of observed behaviors in purified microtubules. Our results establish a new physical foundation for understanding microtubule dynamics and open the door to predictive modeling of cytoskeletal regulation.