Ligand Binding Swaps between
Soft Internal Modes of
α,β-Tubulin and Alters Its Accessible Conformational Space
Sarmistha Majumdar
Shubhra Ghosh Dastidar
10.1021/acs.jpcb.6b11322.s001
https://acs.figshare.com/articles/journal_contribution/Ligand_Binding_Swaps_between_Soft_Internal_Modes_of_-Tubulin_and_Alters_Its_Accessible_Conformational_Space/4487978
The 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.
2016-12-02 00:00:00
microtubule
ligand design
Accessible Conformational Space
dimer
quaternary level
cell division
Soft Internal Modes
tubulin
bias
building block
mechanism
Ligand Binding Swaps
change propagates
multiscale process
unliganded systems
breathing modes