title: Ligand Binding Swaps between Soft Internal Modes of α,β-Tubulin and Alters Its Accessible Conformational Space.
abstract: 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.
authors.affiliation: Bioinformatics Centre, Bose Institute , P-1/12 C.I.T. Scheme VII M, Kolkata 700054, India.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: Bioinformatics Centre, Bose Institute , P-1/12 C.I.T. Scheme VII M, Kolkata 700054, India.
authors.forename: Shubhra
authors.initials: S
authors.lastname: Ghosh Dastidar
mesh_terms: D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D025341:Principal Component Analysis; D011487:Protein Conformation; D014404:Tubulin / Q000737:chemistry*
chemical_list: D008024:Ligands; D014404:Tubulin