# Picosecond Dynamics of a Small Molecule in Its Bound State with an Intrinsically Disordered Protein

## TL;DR

The study shows that a small molecule can dynamically interact with a disordered protein from the hepatitis C virus, challenging the idea that such proteins are hard to target with drugs.

## Contribution

The novel contribution is the experimental demonstration of a small molecule binding to an intrinsically disordered protein with measurable dynamics.

## Key findings

- 5-fluoroindole interacts with the disordered domains of non-structural protein 5A from hepatitis C virus with a Kd of 260 ± 110 μM.
- The rotational correlation time increased from 27.0 ± 1.3 ps in the free state to 46 ± 10 ps in the bound state.
- Small molecules can bind to intrinsically disordered proteins in dynamic ways, unlike rigid binding to structured proteins.

## Abstract

Intrinsically disordered proteins (IDPs) are highly dynamic
biomolecules
that rapidly interconvert among many structural conformations. These
dynamic biomolecules are involved in cancers, neurodegeneration, cardiovascular
illnesses, and viral infections. Despite their enormous therapeutic
potential, IDPs have generally been considered undruggable because
of their lack of classical long-lived binding pockets for small molecules.
Currently, only a few instances are known where small molecules have
been observed to interact with IDPs, and this situation is further
exacerbated by the limited sensitivity of experimental techniques
to detect such binding events. Here, using experimental nuclear magnetic
resonance (NMR) spectroscopy 19F transverse spin-relaxation
measurements, we discovered that a small molecule, 5-fluoroindole,
interacts with the disordered domains of non-structural protein 5A
from hepatitis C virus with a Kd of 260
± 110 μM. Our analysis also allowed us to determine the
rotational correlation times (τc) for the free and
bound states of 5-fluoroindole. In the free state, we observed
a rotational correlation time of 27.0 ± 1.3 ps, whereas in the
bound state, τc only increased to 46 ± 10 ps.
Our findings imply that it is possible for small molecules to engage
with IDPs in exceptionally dynamic ways, in sharp contrast to the
rigid binding modes typically exhibited when small molecules bind
to well-defined binding pockets within structured proteins.