Researchers have modeled every atom in a key part of the process for switching on genes, revealing a whole new area for potential drug targets [Weinzierl and Scholes/Imperial College London]
The discrete regulatory mechanisms that control gene expression are critical for proper protein production and overall cell viability. Yet, in numerous cases, errors within the genetic code lead to faulty manufacturing of proteins—resulting in genetic diseases like cystic fibrosis and hemophilia. Transcription factors, which moderate gene expression, bind to the start of a gene sequence at its basal machinery, telling it to switch on and start creating certain proteins. However, the mechanisms that transcription factors employ to bind to this basal machinery are a “fuzzy” process, meaning the exact sequence of events is unknown because the regulatory steps occur so rapidly that they are next to impossible to capture by traditional imaging techniques.
By creating a computer simulation of all of the tens of thousands of atoms that constitute the entire process and modeling their movements in 50 million separate steps, researchers at Imperial College London have now been able to determine the sequence of events that lead to genes being switched on.
“For the first time, we can fill in the dynamic landscape of interaction between transcription factors and basal machinery,” explained Robert Weinzierl, Ph.D., reader in molecular biology in the department of life sciences at Imperial College London. “This is a central mechanism for gene expression—the interactions here determine whether a gene gets switched on and creates proteins.”
The findings from this study were published recently in PLoS Computational Biology through an article entitled “Molecular Dynamics of “Fuzzy” Transcriptional Activator–Coactivator Interactions.”
The simulated process that the research team created revealed pockets within the gene basal machinery, which the transcription factors use to 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.
“Gene regulation is a completely new drug target that has previously been too challenging to explore,” Dr. Weinzierl noted. “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 to build up a picture of the structures involved that changes every couple of femtoseconds—quadrillionths of a second.
“Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 transcriptional ADs [activation domains] and variants thereof, either free in solution, or bound to the GAL11 coactivator surface,” wrote the authors. “We show that the AD–coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of the orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points.”
The research team has submitted a patent application for their computer-based approach to studying gene expression interactions. Using this method, 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,” Dr. Weinzierl concluded.