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Telomere repeat sequence (TRS) DNA is found at the termini of most eukaryotic chromosomes. The sequences are highly repetitive and G-rich (e.g., [C1–3A/TG1–3]n for the yeast Saccharomyces cerevisiae) and are packaged into nonnucleosomal protein-DNA structures in vivo. We have used total intensity light scattering and electron microscopy to monitor the effects of yeast TRS inserts on in vitro DNA condensation by cobalt (III) hexaammine. Insertion of 72 bp of TRS into a 3.3-kb plasmid depresses condensation as seen by light scattering and results in a 22% decrease in condensate thickness as measured by electron microscopy. Analysis of toroidal condensate dimensions suggests that the growth stages of condensation are inhibited by the presence of a TRS insert. The depression in total light scattering intensity is greater when the plasmid is linearized with the TRS at an end (39–49%) than when linearized with the TRS in the interior (18–22%). Circular dichroism of a 95-bp fragment containing the TRS insert gives a spectrum that is intermediate between the A-form and B-form, and the anomalous condensation behavior of the TRS suggests a noncanonical DNA structure. We speculate that under conditions in which the plasmid DNA condenses, the telomeric insert assumes a helical geometry that is similar to the A-form and is incompatible with packing into the otherwise B-form lattice of the condensate interior.

pH-activated, proton selective channels are required during viral entry and replication of influenza viruses. We determined the high resolution structures of proton channels from influenza A and B viruses by solution NMR spectroscopy. The channel structures reveal pore features that are important for proton gating and proton relay. Structural details of the anti-influenza drug, rimantadine, bound to the channel suggests an unexpected allosteric mechanism of drug inhibition and drug resistance, which has been verified by thorough functional and mutagenesis experiments.The work is supported by NIH grant AI067438.

Signal transduction is essential for many biological processes, such as mitosis, cell regeneration, and muscle contraction. Muscle-Specific Kinase (MuSK) is in a complex with low-density lipoprotein receptor-related protein 4 (LRP4), and upon binding of the substrate Agrin to LRP4, conformational changes of these proteins initiate a signalling cascade, stimulating aggregation of acetylcholine receptors (AChRs), which results the downstream organization of neuromuscular synapses. Mutations and/or autoantibodies against MuSK affects its ability to aggregate acetylcholine receptors, resulting in the disease myasthenia gravis, which is characterised by impaired muscle contractions. Approximately 70% of the structure of the full-length MuSK protein has been determined (consisting of the most of the extracellular domain and the intracellular kinase domain). However, crucially the transmembrane domain has not been characterised, and the structure of the transmembrane dimer that MuSK forms has not been determined. Here we apply a multi-scale MD simulation method to examine at the behaviour of MuSK TM helices in a lipid bilayer vs. a detergent micelle environment. Coarse-grained (CG) simulations, which make an extended timescale readily accessible, are used to examine initial TM helix dimerisation events. Subsequent atomistic simulations serve to refine the model of the interactions observed in CG simulations. These computational studies highlight the effect of lipids vs. detergents on the interactions of the transmembrane helices within the dimer.