Computational investigation of pLGICs interacting with general anesthetics is surprisingly tricky. This article/chapter provides guidelines for reproducing the approach that we’ve refined over a decade. Sruthi gives some warnings for avoiding docking pitfalls and tips on running unbiased (traditional) molecular dynamics simulation. For more advanced users, she provides steps for rigorously calculating binding affinities and testing convergence.
Our new book chapter (in a great volume edited by Irena Levitan at the University of Illinois at Chicago) reviews our simulations of cholesterol and other sterols interacting with pLGICs. It also includes a brief teaser of Liam’s new coarse-grained simulations involving nAChRs in phase-separated quasi-neuronal membranes, and offers some simulation-inspired ideas for experiments with straightforward interpretations.
It’s official. Much appreciation to all who helped along the way – students, postdocs, collaborators, colleagues, referees, program officers, friends, mentors, family.
Kristen Woods, a Masters student in Computational and Integrative Biology has joined the group! Kristen was also here at Rutgers-Camden for her undergraduate degree and decided to stay at our unique campus for graduate school. She will add to the group’s growing ‘coarse-grained’ arm, which simulates complex neuronal membranes over longer length and time scales.
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!
The Brannigan group is looking for summer interns! Please check out the Job Description :
One or more summer research positions for undergraduates are available in the Brannigan Research Group at Rutgers University (Camden Campus).
The research in the group is done entirely on the computer; we use equations from classical physics to simulate the dynamics of molecular systems that are relevant to biology and medicine, but experimentally inaccessible. Summer research students would be working on simulations of mixed membranes (lipid bilayers) containing neurotransmitter receptors.
The research group includes students with a range of STEM backgrounds. You might be a good match for this position if you are:
– A physics or chemistry major, interested in biology, and comfortable using computers, particularly linux.
– An upper-level biology major that has taken at least one year of college physics, and enjoys using computers.
– A computer science major that has taken at least one year of college physics, is enthusiastic about scientific questions, and comfortable using linux.
– A student with a different background, but with related interests and the ability to learn quickly.
We’re located on the Camden campus of Rutgers University – a friendly and pretty campus just across the Delaware River from Philadelphia, adjacent to the Camden waterfront and next to the City Hall PATCO station.
Internship is for eight weeks, from June 20 – August 5, 2016 (some flexibility on start and/or end date is available.), and includes a stipend.
Interested students should check out the lab webpage at https://branniganlab.wordpress.com , then send a CV/resume and a brief explanation of their interest to email@example.com
Liam successfully defended his Computational & Integrative Biology Masters thesis on Thursday, April 28, 2016. He will be continuing his research on interactions of nicotinic acetylcholine receptors with mixed membranes as a PhD student.