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The group was very well-represented at this year’s CCIB Best Student Paper Contest. Ruchi tied for first place with her paper Sequence specificity despite intrinsic disorder: How a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein and Liam was awarded third place for his paper Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation. Ruchi and Liam competed against a record number of entries this year, and this is well-deserved recognition for two great papers. Congratulations!
Collaborative work with the Hill lab at University of Basel was just published in Structure! “The Structural Basis for Low Conductance in the Membrane Protein VDAC upon β-NADH Binding and Voltage Gating” used NMR, electrophysiology, and atomistic MD simulations to study the mitochondrial ion channel VDAC. VDAC is a beta-barrel protein with a much larger and less-sensitive pore than the ligand-gated ion channels we also study. For channels with very narrow pores, understanding how conduction starts can be tricky, but for VDAC it is harder to understand why conduction ever stops. Sruthi and Shashank contributed atomistic MD simulations of NMR structures solved by the Hill lab.
Jesse Sandberg, an MS student in the Graduate Program in Computational and Integrative Biology, is joining the group. Jesse will be using free energy calculations to predict whether small molecules like insecticides, antibiotics, and candidate drugs will block human GABA(A) receptors, causing neurotoxicity. Welcome, Jesse!
Collaborative work with the Cheng lab at Washington University-St Louis was just published in eLife! “Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel” used electrophysiology, mass spectrometry, and coarse-grained simulations. The work demonstrates quantitatively that the prokaryotic pentameric-ligand gated ion channel ELIC sorts membrane lipids to increase the number of charged-lipid headgroups (particularly phosphatidylglycerol headgroups) in its vicinity. Liam contributed coarse-grained MD simulations of ELIC in multiple lipid mixtures, with results that corresponded remarkably well to the experimental data.
Collaborative work with the Baenziger and Ulens labs was just published in Nat Chem Bio! “A lipid site shapes the agonist response of a pentameric ligand-gated ion channel” investigates the role of specifically-bound lipids in gating a neurotransmitter receptor. Kristen contributed atomistic simulations of structures from the Ulens lab.
Ruchi’s paper “Sequence Specificity Despite Intrinsic Disorder : How a Disease-Associated Val/Met Polymorphism Rearranges Tertiary Interactions in a Long Disordered Protein” was just published in PLOS Computational Biology! This paper focuses on a common variation in Brain-derived Neurotrophic Factor (BDNF). About 70% of the US population has two copies of the “V” form of the protein, 25% has one copy of the “V” form and one copy of the “M” form, and 5% has two copies of the “M” form. The particular copies you have can affect how you store memories and respond to stress.
The region of the protein containing the variant is disordered, and normally we would expect the “V” and “M” forms to behave very similarly. It was unclear why this small change would make any difference at all. In this paper we found that although the two forms do interact similarly with water, the “M” form (on the right) introduces a specific “Met-Met” interaction. We often don’t consider Met-Met interactions, even though they are common in structured proteins. Here we showed that they can also affect the behavior of disordered proteins, which in turn contributes to the natural variation among human brains.
Ruchi successfully defended her PhD thesis “Predicting the effect of genetic variance on the sequence-ensemble relationship of intrinsically disordered proteins.” Ruchi’s thesis used techniques ranging from sophisticated simulations requiring millions of supercomputing hours, to bioinformatics surveys of thousands of proteins.
During her thesis, Ruchi produced thousands of plots, diagrams, and figures in an effort to understand why a seemingly subtle change can have substantial effects. Then she did much harder work: left most of these figures on her hard-drive, and selected a compelling few that revealed a very cool scientific story. Congratulations, Ruchi!
A paper resulting from a collaboration between the Brannigan group and the Joseph Martin group in Rutgers-Camden Biology has just been published! “L-3,3’,5-triiodothyronine and pregnenolone sulfate inhibit Torpedo nicotinic acetylcholine receptors” is primarily an experimental paper that tests hypotheses about how the electrostatic charge of hormones changes their effects on acetylcholine receptors.
Understanding this information helps clarify why certain molecules bind to these receptors and others don’t, which is important for designing new molecules like drugs.
The study takes advantage of a very convenient property of thyroid hormone: thyroid hormone changes its charge (or protonation state) with a very slight decrease in physiological pH. The experiments were mainly carried out by Steven Moffett, a PhD student in the Martin Lab. Congratulations Steve!
Rulong successfully defended his Masters thesis “The effect of phospholipid species on non-ideal behavior in cholesterol-containing bilayers”! He’ll be moving on to the PhD Program in Biochemistry at the University of Houston, in Fall 2019. Congratulations, Rulong!
Congratulations to Kristen and Liam – their paper Untangling direct and domain-mediated interactions between nicotinic acetylcholine receptors in DHA-rich membranes was accepted to the Journal of Membrane Biology! This paper builds on Liam’s previous results that nAChR boundary lipids are enriched for polyunsaturated acids (PUFAs) in membranes that form domains, like the white lipids in the top row. Here we tested whether this was still true if the PUFA-rich domains could not form (bottom row), as well as how domain formation affects oligomerization of nAChRs. nAChRs seem to be corralled by the domains, so they dimerize at lower protein concentrations.