Discrimination of Ligands
with Different Flexibilities
Resulting from the Plasticity of the Binding Site in Tubulin
- Publication date
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Abstract
Tubulin, an α,β heterodimer, has four distinct
ligand
binding sites (for paclitaxel, peloruside/laulimalide, vinca, and
colchicine). The site where colchicine binds is a promising drug target
for arresting cell division and has been observed to accommodate compounds
that are structurally diverse but possess comparable affinity. This
investigation, using two such structurally different ligands as probes
(one being colchicine itself and another, TN16), aims to provide insight
into the origin of this diverse acceptability to provide a better
perspective for the design of novel therapeutic molecules. Thermodynamic
measurements reveal interesting interplay between entropy and enthalpy.
Although both these parameters are favourable for TN16 binding (Δ<i>H</i> < 0, Δ<i>S</i> > 0), but the magnitude
of entropy has the determining role for colchicine binding as its
enthalpic component is destabilizing (Δ<i>H</i> >
0, Δ<i>S</i> > 0). Molecular dynamics simulation
provides
atomistic insight into the mechanism, pointing to the inherent flexibility
of the binding pocket that can drastically change its shape depending
on the ligand that it accepts. Simulation shows that in the complexed
states both the ligands have freedom to move within the binding pocket;
colchicine can switch its interactions like a “flying trapeze”,
whereas TN16 rocks like a “swing cradle”, both benefiting
entropically, although in two different ways. Additionally, the experimental
results with respect to the role of solvation entropy correlate well
with the computed difference in the hydration: water molecules associated
with the ligands are released upon complexation. The complementary
role of van der Waals packing versus flexibility controls the entropy–enthalpy
modulations. This analysis provides lessons for the design of new
ligands that should balance between the “better fit”
and “flexibility”’, instead of focusing only
on the receptor–ligand interactions