Simulating PIP2-Induced Gating Transitions in Kir6.2 Channels.

ATP-sensitive potassium (KATP) channels consist of an inwardly rectifying K+ channel (Kir6.2) pore, to which four ATP-sensitive sulfonylurea receptor (SUR) domains are attached, thereby coupling K+ permeation directly to the metabolic state of the cell. Dysfunction is linked to neonatal diabetes and other diseases. K+ flux through these channels is controlled by conformational changes in the helix bundle region, which acts as a physical barrier for K+ permeation. In addition, the G-loop, located in the cytoplasmic domain, and the selectivity filter might contribute to gating, as suggested by different disease-causing mutations. Gating of Kir channels is regulated by different ligands, like Gßγ, H+, Na+, adenosine nucleotides, and the signaling lipid phosphatidyl-inositol 4,5-bisphosphate (PIP2), which is an essential activator for all eukaryotic Kir family members. Although molecular determinants of PIP2 activation of KATP channels have been investigated in functional studies, structural information of the binding site is still lacking as PIP2 could not be resolved in Kir6.2 cryo-EM structures. In this study, we used Molecular Dynamics (MD) simulations to examine the dynamics of residues associated with gating in Kir6.2. By combining this structural information with functional data, we investigated the mechanism underlying Kir6.2 channel regulation by PIP2.

Rethinking the interplay between affluence and vulnerability to aid climate change adaptive capacity.

Affluence and vulnerability are often seen as opposite sides of a coin-with affluence generally understood as reducing forms of vulnerability through increased resilience and adaptive capacity. However, in the context of climate change and an increase in associated hazards and disasters, we suggest the need to re-examine this dynamic relationship-a complex association we define here as the Affluence-Vulnerability Interface (AVI). We review research in different national contexts to show how a more nuanced understanding of the AVI can (a) problematize the notion that increasing material affluence necessarily has a mitigating influence on social vulnerability, (b) extend our analysis of social vulnerability beyond low-income regions to include affluent contexts and (c) improve our understanding of how psychosocial characteristics influence people's vulnerability. Finally, we briefly outline three methodological approaches that we believe will assist future engagement with the AVI.

Computational Insights Into Voltage Dependence of Polyamine Block in a Strong Inwardly Rectifying K+ Channel.

Inwardly rectifying potassium (KIR) channels play important roles in controlling cellular excitability and K+ ion homeostasis. Under physiological conditions, KIR channels allow large K+ influx at potentials negative to the equilibrium potential of K+ but permit little outward current at potentials positive to the equilibrium potential of K+, due to voltage dependent block of outward K+ flux by cytoplasmic polyamines. These polycationic molecules enter the KIR channel pore from the intracellular side. They block K+ ion movement through the channel at depolarized potentials, thereby ensuring, for instance, the long plateau phase of the cardiac action potential. Key questions concerning how deeply these charged molecules migrate into the pore and how the steep voltage dependence arises remain unclear. Recent MD simulations on GIRK2 (=Kir3.2) crystal structures have provided unprecedented details concerning the conduction mechanism of a KIR channel. Here, we use MD simulations with applied field to provide detailed insights into voltage dependent block of putrescine, using the conductive state of the strong inwardly rectifying K+ channel GIRK2 as starting point. Our µs long simulations elucidate details about binding sites of putrescine in the pore and suggest that voltage-dependent rectification arises from a dual mechanism.

Dynamics of the EAG1 K+ channel selectivity filter assessed by molecular dynamics simulations.

EAG1 channels belong to the KCNH family of voltage gated potassium channels. They are expressed in several brain regions and increased expression is linked to certain cancer types. Recent cryo-EM structure determination finally revealed the structure of these channels in atomic detail, allowing computational investigations. In this study, we performed molecular dynamics simulations to investigate the ion binding sites and the dynamical behavior of the selectivity filter. Our simulations suggest that sites S2 and S4 form stable ion binding sites, while ions placed at sites S1 and S3 rapidly switched to sites S2 and S4. Further, ions tended to dissociate away from S0 within less than 20 ns, due to increased filter flexibility. This was followed by water influx from the extracellular side, leading to a widening of the filter in this region, and likely non-conductive filter configurations. Simulations with the inactivation-enhancing mutant Y464A or Na+ ions lead to trapped water molecules behind the SF, suggesting that these simulations captured early conformational changes linked to C-type inactivation.

Dealing with the white death: avalanche risk management for traffic routes.

This article discusses mitigation strategies to protect traffic routes from snow avalanches. Up to now, mitigation of snow avalanches on many roads and railways in the Alps has relied on avalanche sheds, which require large initial investments resulting in high opportunity costs. Therefore, avalanche risk managers have increasingly adopted organizational mitigation measures such as warning systems and closure policies instead. The effectiveness of these measures is, however, greatly dependent on human decisions. In this article, we present a method for optimizing avalanche mitigation for traffic routes in terms of both their risk reduction impact and their net benefit to society. First, we introduce a generic framework for assessing avalanche risk and for quantifying the impact of mitigation. This allows for sound cost-benefit comparisons between alternative mitigation strategies. Second, we illustrate the framework with a case study from Switzerland. Our findings suggest that site-specific characteristics of avalanche paths, as well as the economic importance of a traffic route, are decisive for the choice of optimal mitigation strategies. On routes endangered by few avalanche paths with frequent avalanche occurrences, structural measures are most efficient, whereas reliance on organizational mitigation is often the most appropriate strategy on routes endangered by many paths with infrequent or fuzzy avalanche risk. Finally, keeping a traffic route open may be very important for tourism or the transport industry. Hence, local economic value may promote the use of a hybrid strategy that combines organizational and structural measures to optimize the resource allocation of avalanche risk mitigation.