Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

Our study provides an example where atomic level structural information is used as the sole input to predict cellular level dynamics without parameter adjustment

Mahya Hemmat; David J. Odde

2021

Scholarcy highlights

  • Biological processes occur over a wide range of spatial and temporal scales, spanning from angstroms and picoseconds at the atomistic level to micrometers and minutes at the cellular level
  • We find that the GTP-tubulin longitudinal bond has a stronger potential of mean force than GDP-tubulin by DUlong % 6.6 ± 2.8 kBT, which translates into a standard Gibbs free energy difference of % 4 ± 0.5 kBT
  • To investigate the longitudinal interaction between tubulin heterodimers, an interaction essential to protofilament formation, we modeled a pair of tubulin dimers stacked longitudinally via molecular dynamics simulations
  • We investigated the fundamental atomistic and molecular mechanics underlying a complex biological phenomenon, microtubule dynamic instability, by using a multiscale approach, integrating structural, mechanochemical, and kinetic perspectives that span from atoms to cellular scales
  • We find that a longitudinal bond difference is insufficient by itself to produce the experimentally observed tapered growing tip structures, and a nucleotide-dependent radial preferred angle is essential to recreate curling protofilaments commonly found at the tips of shortening microtubules and blunt tip structures in growing microtubules
  • By using this multiscale approach without parameter adjustment, we conclude that dynamic instability occurs primarily by weakening of the longitudinal bond and secondarily by outward curling between dimers upon GTP hydrolysis in the microtubule lattice
  • Nucleotide-dependent lateral and longitudinal bonds, with GDP-tubulin having a stronger longitudinal and a weaker lateral bond, suggested by a recent cryo-electron microscopy study were ruled out based on the results of multiscale model and our previous molecular dynamics studies of the lateral bond potential of mean force.77 It was only the addition of a radial bending preference to our nucleotide-dependent longitudinal bond in our model that captured both predicted microtubule dynamics and tip structures

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