Researchers have modelled every atom in a key part of the
process for switching on genes, revealing a whole new area for
potential drug targets.
Proteins are essential for processes that sustain life. They are
created in cells through a process called gene expression, which
uses instructions from stretches of DNA called genes to build
proteins. Sometimes genes are faulty and create proteins that
contain errors, preventing the cell from functioning properly.
These lead to genetic diseases like cystic fibrosis and
haemophilia.
Gene expression is controlled by molecules called transcription
factors, which bind to the start of a gene sequence at its 'basal
machinery' and tell it to switch on and start creating certain
proteins.
The way transcription factors bind to the basal machinery is a
'fuzzy' process, meaning the exact sequence of events is unknown
because the steps do not exist for long enough to be captured by
traditional imaging techniques.
But now, by creating a computer simulation of all of the tens of
thousands of atoms making up the process and modelling their
movements in 50 million separate steps, researchers at Imperial
College London have been able to determine the sequence of events
that lead to genes being switched on.
The simulated process revealed 'pockets' in the gene basal
machinery, which the transcription factors move in and out of
during binding. Knowing how these structures fit together could
lead to the design of molecules that interfere with or disrupt the
process, potentially tackling diseases.
Lead researcher Dr Robert Weinzierl from Imperial's Department
of Life Sciences said: "For the first time, we can fill in the
dynamic landscape of interaction between transcription factors and
basal machinery. This is a central mechanism for gene expression -
the interactions here determine whether a gene gets switched on and
creates proteins.
"Gene regulation is a completely new drug target that has
previously been too challenging to explore. This process influences
biology on a really fundamental level, and could allow us to
prevent the expression of detrimental genes."
The researchers' new technique predicts the movements of all the
atoms in order to build up a picture of the structures involved
changing every couple of femtoseconds - quadrillionths of a
second.
Dr Weinzierl has submitted a patent application for his
computer-based approach to studying gene expression interactions.
Using this, compounds could be screened for possible fit into the
basal machinery pockets.
"With computer simulation, it becomes easy to identify candidate
compounds that could target these interactions without the need to
test them first in real life, cutting down the time required to
sift for new drugs," said Dr Weinzierl.
The paper, Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator
Interaction's, is published in PLOS Computational
Biology.