BPS2026 – Modeling structural changes in E-hooks due to length and post-translational modifications

Microtubules (MTs) are dynamic cytoskeletal polymers composed of α/β-tubulin heterodimers, each bearing intrinsically disordered C-terminal tails known as E-hooks. These highly negative ends play critical roles in regulating MT behavior by modulating interactions with microtubule-associated proteins (MAPs), motor proteins, and other cellular factors. Their versatility arises from a combination of isotype diversity and a complex array of post-translational modifications (PTMs), forming the “tubulin code” regulatory language. Despite their importance, the structural and dynamic properties of E-hooks remain elusive due to their intrinsic disorder. Our previous work addressed this challenge by using quantum mechanical calculations to analyze six residue long E-hook fragments, reducing computational cost while revealing residue specific behaviors and side chain interactions at atomic resolution. However, these truncated models cannot capture the emergent properties that arrive from a more developed tail, including distributed charge effects, long range intramolecular interactions, and the influence of PTMs on global conformation. Here, we extend this approach to construct complete β-tubulin E-hook models, showing how the more consistently negative N-terminal residues affected the more varied C-terminal tips of E-hooks which are more prone to secondary structure formation. Incorporation of biologically relevant PTMs further reveals how modifications reshape electrostatic landscapes, alter transient secondary structures, and potentially modulate MAP and motor protein binding interfaces. This holistic modeling strategy uncovers principles of E-hook regulation that are inaccessible through fragment level studies, providing a mechanistic framework for understanding how sequence context and chemical modifications together encode functional outcomes within the tubulin code.