PDBid:3RIF. Image made using PyMOL
How can Molecular Dynamics help in controlling pests? Well, insects have something called resistant to dieldrin receptor or RDL receptors. These are part of a big family of receptors called Cys-loop receptors. Insecticides invariably bind to these receptors and in turn affect the neurotransmission in the pest. So, it becomes imperative to understand these receptors in order to develop and rationally design insecticides that are highly specific.
Molecular Dynamics are part and parcel of the toolkit for a structural bioinformatician. Whether it is for relaxing a structure or for analyzing complex stuff. Most often, they are used in scenarios where a single amino acid mutation is made in the protein. Coupled it with homology modeling and docking the picture gets perfect.
Ashby et al published their work that incorporates MD, Homology modeling and docking studies to the RDL receptor. The most often used rules in homology modeling are “Alignment, Alignment, Alignment”, and when the sequence identity to the closest invertebrate homolog for RDL receptor is 38.1% it definitely raises a flag/concern. That’s most likely the place MD plays a role in relaxing the structure. Moreover, MD done after ligand docking to a homology modeled structure resolves, to a large extent, the noise/false positives that the prediction methods incorporate. This strategy is useful when ligand bound x-ray structures are hard to obtain due to many reasons. And, this has been the approach for the study published by Ashby et al.
Using this approach, conserved residues that contribute towards GABA binding were confirmed, and also other residues’ role in binding were found. When the significance of these residues were found via multiple MD simulations, mutagenesis studies confirmed their role in specific binding.
Thus, combining previously known functional data, mutagenesis, and simulation (MD and docking) data the residues R111, E204, F206, Y254, and R256 were identified to be highly critical for the activity of RDL receptor. Now, this new study definitely will be giving jitters to the pest!
Reference:
Ashby, J., McGonigle, I., Price, K., Cohen, N., Comitani, F., Dougherty, D., Molteni, C., & Lummis, S. (2012). GABA Binding to an Insect GABA Receptor: A Molecular Dynamics and Mutagenesis Study Biophysical Journal, 103 (10), 2071-2081 DOI: 10.1016/j.bpj.2012.10.016
Getting to know Structural Bioinformatics 