Multi-scale Computational Modeling of Tubulin-Tubulin Lateral Interaction

Abstract

Microtubules are multi-stranded polymers in eukaryotic cells that support key cellular functions such as chromosome segregation, motor-based cargo transport, and maintenance of cell polarity. Microtubules self-assemble via \"dynamic instability,\" where the dynamic plus ends switch stochastically between alternating phases of polymerization and depolymerization. A key question in the field is what are the atomistic origins of this switching, i.e. what is different between the GTP- and GDP-tubulin states that enables microtubule growth and shortening, respectively? More generally, a major challenge in biology is how to connect theoretical frameworks across length-time scales, from atoms to cellular behavior. In this study, we describe a multi-scale model by linking atomistic molecular dynamics (MD), molecular Brownian dynamics (BD), and cellular-level thermo-kinetic (TK) modeling of microtubules. Here we investigated the underlying interaction energy landscape when tubulin dimers associate laterally by performing all-atom molecular dynamics simulations. We found that the lateral free energy is not significantly different among three nucleotide states of tubulin, GTP, GDP, and GMPCPP, and is estimated to be {cong}-11 kBT. Furthermore, using MD potential energy in our BD simulations of tubulin dimers in solution confirms that the lateral bond is weak on its own with a mean lifetime of ~0.1 s, implying that the longitudinal bond is required for microtubule assembly. We conclude that nucleotide-dependent lateral bond strength is not the key mediator microtubule dynamic instability, implying that GTP acts elsewhere to exert its stabilizing influence on microtubule polymer. Furthermore the estimated bond strength is well-aligned with earlier estimates based on thermokinetic (TK) modeling and light microscopy measurements (VanBuren et al., PNAS, 2002). Thus, we have computationally connected atomistic level structural information, obtained by cryo-electron microscopy, to cellular scale microtubule assembly dynamics using a combination of MD, BD, and TK models to bridge from [A]ngstroms to micrometers and from femtoseconds to minutes.