jp6b11322_si_001.pdf (1.02 MB)
Ligand Binding Swaps between Soft Internal Modes of α,β-Tubulin and Alters Its Accessible Conformational Space
journal contribution
posted on 2016-12-02, 00:00 authored by Sarmistha Majumdar, Shubhra Ghosh DastidarThe dynamic instability
of the microtubule originates from the
conformational switching of its building block, that is, the α,
β-tubulin dimer. Ligands occupying the interface of the α–β
dimer bias the switch toward the disintegration of the microtubule,
which in turn controls the cell division. A little loop of tubulin
is structurally encoded as a biophysical “gear” that
works by changing its structural packing. The consequence of such
change propagates to the quaternary level to alter the global dynamics
and is reflected as a swapping between the relative contributions
of dominating internal modes. Simulation shows that there is an appreciable
separation between the conformational space accessed by the liganded
and unliganded systems; the clusters of conformations differ in their
intrinsic tendencies to “bend” and “twist”.
The correlation between the altered breathing modes and conformational
space rationally hypothesizes a mechanism of straight−bent
interconversion of the system. In this mechanism, a ligand is understood
to bias the state of the “gear” that detours the conformational
equilibrium away from its native preference. Thus, a fundamental biophysical
insight into the mechanism of the conformational switching of tubulin
is presented as a multiscale process that also shows promise to yield
newer concept of ligand design.