“A streamlined, general approach for computing ligand binding free energies and its application to GPCR-bound cholesterol” was just accepted to J. Chem Theory and Computation.
Alchemical free energy perturbation is a rigorous but delicate technique the lab uses frequently for measuring ligand binding affinities. This paper has an updated and simplified approach that we’ve developed over many years. This approach even works for non-dilute reference state or a complex, phase-separated bulk!
Is it only useful for these complicated systems? Nope! We first had to simplify many of the “usual” steps to even think about adding this complexity on top – so we’ve made the usual steps more robust, even for a protein in a dilute aqueous solution.
This paper has a lot of different pieces. It might seem like it is a complicated paper to be advertising a simple streamlined approach! We did need to tie multiple viewpoints and frameworks together in the paper and provide one treatment that resolved several inconsistencies. While this was a lot of work for us (and makes for a comprehensive paper), we hope using the approach and interpreting the results will be far less work for you!
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.
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.