Allosteric Communication in the Tubulin Dimer Revealed through Molecular Dynamics and Network Analysis

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Abstract
Microtubules are dynamic polymers essential for intracellular organization, with basic constituents being αβ-tubulin dimers. Microtubule growth and shrinkage is tightly regulated by GTP hydrolysis in β-tubulin, yet how the information about the bound nucleotide propagates across the tubulin dimer, beyond its direct binding site, remains unclear. Here we combine extensive all-atom molecular dynamics simulations of αβ-tubulin dimers with GTP or GDP in the β-subunit to investigate longitudinal allosteric signaling. We featurize conformations using residue-wise minimum distances between the two subunits, apply EncoderMap dimensionality reduction and HDBSCAN clustering to identify conformational substates, and perform dynamic network analysis on these clusters. We find that the tubulin dimer relaxes from the straight starting structures into a broad ensemble of bent conformations, and that the bound nucleotide does not by itself separate this ensemble. The simulations retain a comparatively long-lived memory of their starting structure that makes the subtler nucleotide signal harder to detect. Network analysis identifies residues that are most important for information flow, as well as preferred communication routes across the longitudinal interface. Substate-specific analysis indicates that the transition from the GTP- to GDP-bound state is associated with changes in the preferred allosteric routes, enhancing our understanding of longitudinal communication in tubulin. Beyond tubulin, our approach illustrates how combining dimensionality reduction with substate-specific network analysis can uncover hidden allosteric signatures in protein assemblies.

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