New paper on q-bio on calculations of binding affinities using alchemical free energy perturbation (updated May 2018)
[Update to Submission version May 2018: Substantial simplification of the theory/formalism sections for readability, improved incorporation of quadratic mixture model.]
Alchemical free energy perturbation is a rigorous technique the lab uses frequently for measuring ligand binding affinities. This new paper has an updated and simplified approach that we’ve developed over many years – motivated by challenges in measuring and interpreting binding affinities for membrane proteins. This approach even works for non-dilute reference state or a complex, phase-separated bulk! We’ve also included calculation of cholesterol affinities for 3 different GPCRs as a sample application.
The preference of the nicotinic acetylcholine receptor (nachr) for certain lipid environments has been a subject of debate for decades. This new paper under review at BBA-Biomembranes uses coarse-grained molecular dynamics to equilibrate the local lipid environment around an nAChR in a ternary membrane mixture. We find a high affinity of omega-3 fatty acids (like those found in fish oil) for the nAChR interface with the membrane. This suggests there could be specific interactions with nAChR that underly the benefits of fish oil for function of the central nervous system.
Kristen gave an excellent defense of her MS dissertation “Oligomerization of nicotinic acetylcholine receptors in coarse-grained model membranes” and is now continuing on to complete her PhD in the lab.
Sruthi successfully defended her thesis “Mechanisms underlying effects of genetic variance and general anesthetics on pentameric ligand-gated ion channels” to receive the first Brannigan Lab PhD. She set a strong precedent, by tackling technically challenging problems, uncovering unintuitive mechanisms, publishing a number of papers, and producing some very compelling movies in the process. Congratulations, Sruthi – we are all proud!
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.