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We were thrilled to hear that Group Alumni Shashank Chavali (MS 2016) just defended his PhD dissertation “Use of Lab-Evolved Proteins to Guide Development of Inhibitors that Target HIV-1 TAR RNA” at the University of Rochester. He will be moving on to a joint postdoc between the Sindelar and the De La Cruz labs at Yale University, studying motor proteins. Congratulations Dr. Chavali!
Liam’s paper “Spontaneous lipid binding to the nicotinic acetylcholine receptor in a native membrane” has been published! It is a contribution to the JCP Special Collection in Honor of Women in Chemical Physics and Physical Chemistry, and is also the culmination of Liam‘s doctoral research, so it is particularly special to me! This paper uses coarse-grained molecular dynamics and a metric for lipid binding affinities to provide quantitative ranking of specific lipid binding in a very complex membrane. It builds on his previous papers identifying specifically-bound lipids in model membranes.
Tom’s paper investigating binding of ketamine analogues to GPCRs was just published in ACS Chemical Neuroscience! “Ketamine Metabolite (2R,6R)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors” used atomistic MD simulations, streamlined alchemical free energy perturbation calculations, and G-protein recruitment assays to show that a ketamine metabolite is an inverse agonist for two opioid receptors. These results may help explain the mechanism by which ketamine successfully treats treatment-resistant depression. The paper includes a new pharmacological model for binding of ligands with multiple protonation states.
Liam successfully defended his dissertation “Boundary lipids of nicotinic acetylcholine receptors in model and native membranes” in front of his committee, CCIB, and many enthusiastic family members today. He did a fantastic job. We wish him luck at his new postdoc in the lab of Dr. Edward Lyman at the University of Delaware. The lab won’t be the same without you, Liam!
After a successful Fall 2021 rotation cycle, the lab has two new members! We are very excited to welcome Jahmal Ennis and Connor Pitman, who are both graduate students in Computational and Integrative Biology
Jesse Sandberg won the best poster award (MS section) at the 2020 CCIB retreat for his poster “Novel Membrane Bending Mechanism of the Coronavirus Envelope (E) Protein.” The E protein of the coronavirus plays a very important role in shape of the viral envelope, but we don’t know why! Jesse’s poster explored a potential explanation revealed by simulation. Great work!
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.