New article on interactions of general anesthetics with GABA(A) receptors in Journal of Biological Chemistry
Research on the mechanism of general anesthesia from our collaboration with Dr. Roderic Eckenhoff’s group at University of Pennsylvania, is now in press at J Biol Chem:
“A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of GABAA Receptor Subunit Binding Selectivity in Synaptosomes” by Kellie A. Woll, Sruthi Murlidaran, Benika J. Pinch, Jérôme Hénin, Xiaoshi Wang, Reza Salari, Manuel Covarrubias, William P. Dailey, Grace Brannigan, Benjamin A. Garcia, and Roderic G. Eckenhoff.
The experimental side of this work, carried out at Penn and Thomas Jefferson University, involved using click chemistry and photoaffinity labeling to detect differences in binding of the general anesthetic propofol* to subunits forming the GABA(A) receptor. The experiments were done in neurons, where general anesthesia actually takes place.
On the computational side, we used a sophisticated MD technique called Alchemical Free Energy Perturbation to calculate affinities of propofol for sites found in each interface between subunits, and we determined how small changes in the amino acids forming the sites can result in large differences in how strongly the anesthetic binds.
This was challenging because the differences are subtle, but important because GABA(A) receptors across the human central nervous system have many subtle differences with dramatic effects.
*in experiments, actually a propofol analog with modifications necessary for the experimental technique.
Dr Thomas Joseph MD PhD just started a postdoc at Penn in the Anesthesiology department with our collaborators in the Eckenhoff group. Tom is a computational researcher and he’ll be a very active visitor in the Brannigan group, carrying out simulations investigating membrane protein (esp GPCR) pharmacology!
Shashank successfully defended his Masters thesis “Computational Study of NADH Interactions with Voltage Dependent Anion Channel” today! He’ll be moving on to the PhD Program in Biophysics at University of Rochester, in Fall 2016, continuing research on membrane proteins.
Dr. Reza Salari, the group’s first postdoc, is going back into medical practice – he’ll be starting a residency in radiology at Washington University-St Louis next year, and has just left for his year-long internship at Geisinger Hospital. The group will miss him!