General Anesthetics Predicted to Block the GLIC Pore with Micromolar Affinity

Although general anesthetics are known to modulate the activity of ligand-gated ion channels in the Cys-loop superfamily, there is at present neither consensus on the underlying mechanisms, nor predictive models of this modulation. Viable models need to offer quantitative assessment of the relative importance of several identified anesthetic binding sites. However, to date, precise affinity data for individual sites has been challenging to obtain by biophysical means. Here, the likely role of pore block inhibition by the general anesthetics isoflurane and propofol of the prokaryotic pentameric channel GLIC is investigated by molecular simulations. Microscopic affinities are calculated for both single and double occupancy binding of isoflurane and propofol to the GLIC pore. Computations are carried out for an open-pore conformation in which the pore is restrained to crystallographic radius, and a closed-pore conformation that results from unrestrained molecular dynamics equilibration of the structure. The GLIC pore is predicted to be blocked at the micromolar concentrations for which inhibition by isofluorane and propofol is observed experimentally. Calculated affinities suggest that pore block by propofol occurs at signifcantly lower concentrations than those for which inhibition is observed: we argue that this discrepancy may result from binding of propofol to an allosteric site recently identified by X-ray crystallography, which may cause a competing gain-of-function effect. Affinities of isoflurane and propofol to the allosteric site are also calculated, and shown to be 3 mM for isoflurane and for propofol; both anesthetics have a lower affinity for the allosteric site than for the unoccupied pore

Aiming for excellence in STEM learning and teaching proceedings

While maths can be viewed as enabling learning in science and medicine, in reality we see students are bringing their maths anxiety with them to their studies. Our work focuses on dissecting the maths problem as it relates to teaching and learning in these so-called hard disciplines. We have been challenging the inertia of what we see as a stand off with students taking the view that they are unable to do maths and educators frustrated at their disengagement. We have found that the maths problem resonates with several pedagogical frameworks (e.g. Meyer and Land’s Threshold Concepts Framework, Perkins and Simmons’ four frames of understanding) and we have found these useful for unpicking where our students become disengaged. We have applied a number of interventions to assist student learning and are now using our findings to inform the design of an online diagnostic to more explicitly address dysfunctional stances that students adopt when asked to manipulate their quantitative data. Given the extent of the maths problem and the move to increase diversity in the Higher Education sector, we discuss how to enable students to shift to a more positive learning disposition