Abstract
Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of β-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability.
Highlights
Microtubules (MTs) are cellular organelles that participate in major cellular processes such as mitosis, cell shape maintenance, cell motility and motor protein transport and constitute a major target for a wide range of drugs, most notably anti-mitotic chemotherapy agents such as paclitaxel
The molecular machinery of chromosome segregation during cell division is one of the most sophisticated molecular biology mechanisms employing the interplay of different proteins and forces
In our all-atom molecular dynamics simulations we calculated the energy of interactions, within a microtubule cylinder, that is responsible for microtubule stability
Summary
Microtubules (MTs) are cellular organelles that participate in major cellular processes such as mitosis, cell shape maintenance, cell motility and motor protein transport and constitute a major target for a wide range of drugs, most notably anti-mitotic chemotherapy agents such as paclitaxel Due to their importance in cell biology, MTs have been the topic of active research into their structure and function for several decades [1]. Several studies have been conducted to determine which specific structural transitions that accompany GTP hydrolysis or taxol binding are responsible for their effect on MT stability, especially the transition of the tubulin dimer between its straight and curved states [11,12,13,14,15]. A detailed energy balance involving contributions due to each residue, domain or subunit, to the best of our knowledge, was never considered
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