Selectivity Filter Research Articles

Selectivity filter mutations shift ion permeation mechanism in potassium channels.

Potassium (K+) channels combine high conductance with high ion selectivity. To explain this efficiency, two molecular mechanisms have been proposed. The "direct knock-on" mechanism is defined by water-free K+ permeation and formation of direct ion-ion contacts in the highly conserved selectivity filter (SF). The "soft knock-on" mechanism involves co-permeation of water and separation of K+ by water molecules. With the aim to distinguish between these mechanisms, crystal structures of the KcsA channel with mutations in two SF residues-G77 and T75-were published, where the arrangements of K+ ions and water display canonical soft knock-on configurations. These data were interpreted as evidence of the soft knock-on mechanism in wild-type channels. Here, we test this interpretation using molecular dynamics simulations of KcsA and its mutants. We show that while a strictly water-free direct knock-on permeation is observed in the wild type, conformational changes induced by these mutations lead to distinct ion permeation mechanisms, characterized by co-permeation of K+ and water. These mechanisms are characterized by reduced conductance and impaired potassium selectivity, supporting the importance of full dehydration of potassium ions for the hallmark high conductance and selectivity of K+ channels. In general, we present a case where mutations introduced at the critical points of the permeation pathway in an ion channel drastically change its permeation mechanism in a nonintuitive manner.

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Flow cytometry-based quantitative analysis of cellular protein expression in apoptosis subpopulations: A protocol

Flow cytometry techniques utilizing dual staining with annexin V and propidium iodide (PI) provide a robust method for quantitatively analyzing apoptosis induction. Annexin V binds phosphatidylserine exposed on the outer leaflet of the plasma membrane during early apoptosis, while PI permeates late apoptotic/necrotic cells. Simultaneous staining allows differentiation of viable, early apoptotic, and late apoptotic/necrotic populations. This approach can be enhanced by using fluorochrome-conjugated antibodies to stain specific proteins, enabling the simultaneous tracking of protein expression changes in defined cell subpopulations during apoptosis. This multiparametric approach provides key insights into signaling regulation and the mechanisms underlying the apoptotic response to cytotoxic treatments. Here we present a protocol that combines annexin V-FITC/PI staining with APC-conjugated antibody labeling in MDA-MB-231 breast cancer cells treated with doxorubicin. This protocol enables both the quantitative assessment of apoptosis induction and the tracking of decreased CD44 expression from viable to apoptotic cells. This protocol also provides guidelines for appropriate filter selection, compensation controls, gating strategies, and troubleshooting. This robust protocol holds significant potential for elucidating signaling networks involved in apoptosis and therapeutic resistance across various cellular models.

Inibidores da bomba de prótons e sua relação com a microbiota gastrointestinal: O benefício compensa o risco?

Background: This study aimed to investigate the impact of prolonged exposure to PPIs on the gastrointestinal microbiota, as well as to assess its potential implication on the development of gastrointestinal diseases. Methods: This literature review was based on the "National Library of Medicine” (PubMed) research platform, using the descriptors (intestinal microbiota OR gastrointestinal microbiomes OR gut microbiota OR gastrointestinal flora) AND (Proton pump inhibitors OR PPIs). The applied filters for work selection were: published within the last 5 years; written in Portuguese, English, or Spanish; excluding systematic reviews and meta-analyses. Results: Recent studies have revealed a series of alterations in the gastrointestinal microbiota, which have been associated with the exacerbation of pre-existing pathologies or the onset of new conditions. Prolonged use of PPIs has shown considerable impacts on the quantity of gastrointestinal microorganisms such as Streptococcus, Lactobacillus, Bacteroidetes, Veillonellaceae, among others. In addition, an increased incidence of diseases such as hepatic encephalopathy, gastroesophageal reflux disease (GERD), cirrhosis, spontaneous bacterial peritonitis, and intestinal infections have been found. Conclusion: The results showed that the dysbiosis triggered by chronic use of PPIs leads to an increased risk of gastrointestinal diseases. Therefore, it is crucial to adopt a rational prescription of these drugs, carefully considering the risks and benefits to ensure safe and effective use in clinical practice. Furthermore, there is a need for further research to define possible risk groups related to chronic use of PPIs, such as patients with hepatic cirrhosis or hepatitis B

Facile design of a low-cost laser CUT-OFF filter with PMMA polymer nanocomposite doped with Mg0.5Ni0.5Fe2O4: structural, optical, and dielectric properties

This study employed the sol gel auto-combustion approach to synthesize Mg0.5Ni0.5Fe2O4 spinel ferrite nanoparticles. Additionally, the casting method was used to fabricate Mg0.5Ni0.5Fe2O4/PMMA nanocomposite polymer films. The structural properties were analyzed by the utilization of x-ray diffraction pattern (XRD), high resolution transmission electron microscope (HRTEM), and field emission scanning electron microscope (FESEM). The UV-visible spectrophotometer examination was used to evaluate the optical properties of the produced nanocomposite films, such as absorbance, transmittance, indirect energy band gap, Urbach energy, excitation coefficient, and refractive index. Two indirect optical energy gaps are calculated, whereas they decreased from 4.56 eV to 4.33 eV, and from 4.04 eV to 3.01 eV, while the Urbach energy increased from 0.304 eV to 0.524 eV as the nanofillers increased from 0 to 4 wt%. An investigation was conducted to examine the impact of nanoparticle doping on the dielectric constant, electric modulus, and ac conductivity. The Mg0.5Ni0.5Fe2O4/PMMA nanocomposite films demonstrate higher permittivity and ac conductivity and a lower dissipation factor and electric modulus compared to pure PMMA. The dielectric permittivity (ε′) increased from 2.76 to 3.43 at a constant frequency 100 Hz up to 2 wt.% of Mg0.5Ni0.5Fe2O4 then decreased to 2.41 while the dissipation factor tan(δ) decreased from 0.1 to 0.046 at the same frequency. The nanocomposite films are well-suited for utilization in CUT-OFF selective laser filters, solar cells, energy storage devices, and other applications in related industries.

Energy calculations for sodium vs. potassium on a prokaryotic voltage-gated sodium channel: a quantum-chemical study

The selectivity of the sodium channel has been the subject of numerous experimental and theoretical studies. In this work, this problem is approached from a theoretical point of view based on a model built from the Selective Filter (SF) of the open structure of the voltage-activated channel of the bacterium Magnetococcus marinus. This approach has allowed us to calculate the interaction energies of the system (cation-water-SF-fragment), both for the sodium cation and the potassium cation. The results have highlighted the importance of differential dehydration of cations, as well as the environment where it occurs. Semi-empirical and ab initio methods have been applied to analyze and quantify the interaction energies when the cations are in the SF of the sodium channel, with the DFT (ab initio) methods giving us the key to the distribution of the interaction energies and therefore how dehydration occurs.

Exploring Employee Retention among Generation Z Engineers in the Philippines Using Machine Learning Techniques

Generation Z represents a significant portion of the current workforce and is poised to become dominant in the engineering field. As the new generation arises, employee retention becomes a crucial topic in the Philippines. Hence, this study explored the factors influencing employee retention among Generation Z engineers in the Philippines using machine learning feature selection (filter method’s permutation, wrapper method’s backward elimination, and embedded method’s Least Absolute Shrinkage and Selection Operator) and classifiers (support vector and random forest). A total of 412 participants were gathered through a purposive sampling technique. The results showed that six out of seven investigated features were found to be significant factors impacting Generation Z engineers’ intention to remain in a company. These six features were supervisor support, company attachment, job satisfaction, contribution, emotional support, and shared value, organized in descending order of feature importance. These were further explained by fifteen significant subfeatures representing each feature. Only one feature, servant leadership, was deemed insignificant. These findings were extracted from the optimal combination of machine learning algorithms. Particularly, feature selection’s backward elimination brought 85.66% accuracy, and the random forest classifier further enhanced the accuracy value to 90.10%. In addition, the model’s precision, recall, and F1-score values were 89.50%, 90.10%, and 88.90%, respectively. This research also provided practical insights for the company executives, organizational leaders, and human resources department seeking to enhance employee retention strategies. These implications were based on the significant features influencing Generation Z engineers’ retention, ultimately contributing to the long-term success and competitiveness of organizations.

Anesthetic Mechanisms: Synergistic Interactions With Lipid Rafts and Voltage-Gated Sodium Channels.

Despite successfully utilizing anesthetics for over 150 years, the mechanism of action remains relatively unknown. Recent studies have shown promising results, but due to the complex interactions between anesthetics and their targets, there remains a clear need for further mechanistic research. We know that lipophilicity is directly connected to anesthetic potency since lipid solubility relates to anesthetic partition into the membrane. However, clinically relevant concentrations of anesthetics do not significantly affect lipid bilayers but continue to influence various molecular targets. Lipid rafts are derived from liquid-ordered phases of the plasma membrane that contain increased concentrations of cholesterol and sphingomyelin and act as staging platforms for membrane proteins, including ion channels. Although anesthetics do not perturb membranes at clinically relevant concentrations, they have recently been shown to target lipid rafts. In this review, we summarize current research on how different types of anesthetics-local, inhalational, and intravenous-bind and affect both lipid rafts and voltage-gated sodium channels, one of their major targets, and how those effects synergize to cause anesthesia and analgesia. Local anesthetics block voltage-gated sodium channel pores while also disrupting lipid packing in ordered membranes. Inhalational anesthetics bind to the channel pore and the voltage-sensing domain while causing an increase in the number, size, and diameter of lipid rafts. Intravenous anesthetics bind to the channel primarily at the voltage-sensing domain and the selectivity filter, while causing lipid raft perturbation. These changes in lipid nanodomain structure possibly give proteins access to substrates that have translocated as a result of these structural alterations, resulting in lipid-driven anesthesia. Overall, anesthetics can impact channel activity either through direct interaction with the channel, indirectly through the lipid raft, or both. Together, these result in decreased sodium ion flux into the cell, disrupting action potentials and producing anesthetic effects. However, more research is needed to elucidate the indirect mechanisms associated with channel disruption through the lipid raft, as not much is known about anionic lipid products and their influence over voltage-gated sodium channels. Anesthetics' effect on S-palmitoylation, a promising mechanism for direct and indirect influence over voltage-gated sodium channels, is another auspicious avenue of research. Understanding the mechanisms of different types of anesthetics will allow anesthesiologists greater flexibility and more specificity when treating patients.

Molecular mechanism of anion permeation through aquaporin 6

Aquaporins (AQPs) are recognized as transmembrane water channels that facilitate selective water permeation through their monomeric pores. Among the AQP family, AQP6 has an intriguing characteristic as an anion channel, which is allosterically controlled by pH conditions and is eliminated by a single amino acid mutation. However, the molecular mechanism of anion permeation through AQP6 remains unclear. Using molecular dynamics simulations in the presence of a transmembrane voltage utilizing an ion concentration gradient, we show that chloride ions permeate through the pore corresponding to the central axis of the AQP6 homotetramer. Under low pH conditions, a subtle opening of the hydrophobic selectivity filter (SF), located near the extracellular part of the central pore, becomes wetted and enables anion permeation. Our simulations also indicate that a single mutation (N63G) in human AQP6, located at the central pore, significantly reduces anion conduction, consistent with experimental data. Moreover, we demonstrate that the pH-sensing mechanism in which the protonation of H184 and H189 under low pH conditions allosterically triggers the gating of the SF region. These results suggest a unique pH-dependent allosteric anion permeation mechanism in AQP6 and could clarify the role of the central pore in some of the AQP tetramers.

Fine-tuning pH sensor H98 by remote essential residues in the hydrogen-bond network of mTASK-3

TASK-3 generates a background K+ conductance which when inhibited by acidification depolarizes membrane potential and increases cell excitability. These channels sense pH by protonation of histidine residue H98, but recent evidence revealed that several other amino acid residues also contribute to TASK-3 pH sensitivity, suggesting that the pH sensitivity is determined by an intermolecular network. Here we use electrophysiology and molecular modeling to characterize the nature and requisite role(s) of multiple amino acids in pH sensing by TASK-3. Our results suggest that the pH sensor H98 and consequently pH sensitivity is influenced by remote amino acids that function as a hydrogen-bonding network to modulate ionic conductivity. Among the residues in the network, E30 and K79 are the most important for passing external signals near residue S31 to H98. The hydrogen-bond network plays a key role in selectivity or pH sensing in mTASK-3, and E30 and S31 in the network can modulate the conductive properties (E30) or reverse the pH sensitivity and selectivity of the channel (S31). Molecular dynamics simulations and pK1/2 calculation revealed that double mutants involving H98 + S31 primarily regulate the structure stability of the pore selectivity filter and pore loop regions, further strengthen the stability of the cradle suspension system, and alter the ionization state of E30 and K79, thereby preventing pore conformational change that normally occurs in response to varying extracellular pH. These results demonstrate that crucial residues in the hydrogen-bond network can remotely tune the pH sensing of mTASK-3 and may be a potential allosteric regulatory site for therapeutic molecule development.

Vision-related quality of life, photoaversion, and optical rehabilitation in achromatopsia.

We report on photoaversion and patient-reported quality of life in Danish patients with achromatopsia and evaluate the best optical rehabilitation. Our results contribute to the evaluation of outcome measures in therapy trials and aid in providing the best optical rehabilitation for patients with this and clinically similar conditions. This study aimed to investigate the vision-related quality of life, the impact of photoaversion on daily living, and the best optical rehabilitation in a cohort of achromatopsia patients, including testing the hypothesis that red light-attenuating filters are generally preferred. Patients with genetically verified achromatopsia were recruited. Investigations included the 25-item Visual Function Questionnaire and supplementary questions regarding photoaversion and visual aids. Patients were evaluated by a low vision optometrist and given the choice between different light-attenuating filters. First, two specially designed red and gray filters both transmitting 6% light, and then a pre-defined broader selection of filters. Best-corrected visual acuity and contrast sensitivity were measured without filters and with the two trial filters. Twenty-seven patients participated. Median 25-item Visual Function Questionnaire composite score was 73, with the lowest median score in the subscale near vision (58) and the highest in ocular pain (100). The majority of patients (88%) reported that light caused them discomfort, and 92% used aid(s) to reduce light. Ninety-six percent (26 of 27) preferred the gray filter to the red indoors; 74% (20 of 27) preferred the gray filter. Contrast sensitivity was significantly better with the gray filter compared with no filter (p=0.003) and the red filter (p=0.002). Our cohort has a relatively high vision-related quality of life compared with other inherited retinal diseases, but photoaversion has a large impact on visual function. Despite what could be expected from a theoretical point of view, red filters are not generally preferred.

СТРУКТУРА И ПЕРСПЕКТИВЫ ПРИМЕНЕНИЯ В КАЧЕСТВЕ АДСОРБЕНТА ПОРИСТОГО ОКСИДИРОВАННОГО АЛЮМИНИЯ

The paper presents the results of microarc oxidation of porous aluminum made of alloys AlSi15, Д16 (D16) and AlMg6. According to research, on the surface of the sample, a composite oxide-ceramic coating is formed, consisting of mullite 3Al2O3‧2SiO2 and (or) various forms of aluminum oxide (α-, γ-Al2O3). It is shown that on the surface of porous aluminum, as well as in the pores of a cast sample, a coating is formed consisting of electropositive and electronegative sorption materials, aluminum oxides and aluminosilicates. Moreover, by changing the composition of the aluminum alloy and micro-arc oxidation modes, it is possible to control the phase composition of the coating being formed, which opens up the possibility of creating selective filter devices to retain either anionic or cationic inorganic compounds and microbiological objects.

Little evidence of inbreeding depression for birth mass, survival and growth in Antarctic fur seal pups

Inbreeding depression, the loss of offspring fitness due to consanguineous mating, is generally detrimental for individual performance and population viability. We investigated inbreeding effects in a declining population of Antarctic fur seals (Arctocephalus gazella) at Bird Island, South Georgia. Here, localised warming has reduced the availability of the seal’s staple diet, Antarctic krill, leading to a temporal increase in the strength of selection against inbred offspring, which are increasingly failing to recruit into the adult breeding population. However, it remains unclear whether selection operates before or after nutritional independence at weaning. We therefore used microsatellite data from 885 pups and their mothers, and SNP array data from 98 mother–offspring pairs, to quantify the effects of individual and maternal inbreeding on three important neonatal fitness traits: birth mass, survival and growth. We did not find any clear or consistent effects of offspring or maternal inbreeding on any of these traits. This suggests that selection filters inbred individuals out of the population as juveniles during the time window between weaning and recruitment. Our study brings into focus a poorly understood life-history stage and emphasises the importance of understanding the ecology and threats facing juvenile pinnipeds.

Efficient filter pruning: Reducing model complexity through redundancy graph decomposition

Filter pruning has emerged as a crucial technique facilitating the efficient deployment of Convolutional Neural Networks (CNNs) on edge devices. The resultant lightweight models often present a challenging trade-off between performance and compression rate. Moreover, the excessive granularity of filter selection, coupled with intricate fine-tuning procedures, hampers the practical applicability of numerous pruning methodologies. To tackle these limitations, our paper introduces a novel pruning approach that initially constructs an undirected graph, effectively capturing convolutional layer redundancy by quantifying the similarity among output feature maps. Subsequently, our method iteratively eliminates highly redundant and low-value filters, employing both k-core decomposition and importance ranking criteria. In practical implementation, we adopt a one-shot pruning strategy, thereby minimizing the requirement for extensive fine-tuning. Comprehensive comparative experiments demonstrate the efficacy of our proposed approach in achieving remarkable improvements in model compression without compromising performance. For instance, with CIFAR-10, our method achieves state-of-the-art results on DenseNet-40 with a mere 70 fine-tuning epochs, while effectively removing 49.39% of FLOPs, resulting in a mere 0.01% accuracy loss. Furthermore, in the context of ImageNet, our approach excels by removing 48.81% of FLOPs and 23.71% of parameters from ResNet-50, exhibiting only 1.47% and 0.83% decline in Top-1 and Top-5 Accuracy respectively. The code is publicly available at https://github.com/lijiang99/redundancy-graph-decomposition.

Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels

The two-pore domain potassium (K2P) channels TREK-1 and TREK-2 link neuronal excitability to a variety of stimuli including mechanical force, lipids, temperature and phosphorylation. This regulation involves the C-terminus as a polymodal stimulus sensor and the selectivity filter (SF) as channel gate. Using crystallographic up- and down-state structures of TREK-2 as a template for full atomistic molecular dynamics (MD) simulations, we reveal that the SF in down-state undergoes inactivation via conformational changes, while the up-state structure maintains a stable and conductive SF. This suggests an atomistic mechanism for the low channel activity previously assigned to the down state, but not evident from the crystal structure. Furthermore, experimentally by using (de-)phosphorylation mimics and chemically attaching lipid tethers to the proximal C-terminus (pCt), we confirm the hypothesis that moving the pCt towards the membrane induces the up-state. Based on MD simulations, we propose two gating pathways by which movement of the pCt controls the stability (i.e., conductivity) of the filter gate. Together, these findings provide atomistic insights into the SF gating mechanism and the physiological regulation of TREK channels by phosphorylation.

Discovery of Delirium Biomarkers through Minimally Invasive Serum Molecular Fingerprinting.

Delirium presents a significant clinical challenge, primarily due to its profound impact on patient outcomes and the limitations of the current diagnostic methods, which are largely subjective. During the COVID-19 pandemic, this challenge was intensified as the frequency of delirium assessments decreased in Intensive Care Units (ICUs), even as the prevalence of delirium among critically ill patients increased. The present study evaluated how the serum molecular fingerprint, as acquired by Fourier-Transform InfraRed (FTIR) spectroscopy, can enable the development of predictive models for delirium. A preliminary univariate analysis of serum FTIR spectra indicated significantly different bands between 26 ICU patients with delirium and 26 patients without, all of whom were admitted with COVID-19. However, these bands resulted in a poorly performing Naïve-Bayes predictive model. Considering the use of a Fast-Correlation-Based Filter for feature selection, it was possible to define a new set of spectral bands with a wider coverage of molecular functional groups. These bands ensured an excellent Naïve-Bayes predictive model, with an AUC, a sensitivity, and a specificity all exceeding 0.92. These spectral bands, acquired through a minimally invasive analysis and obtained rapidly, economically, and in a high-throughput mode, therefore offer significant potential for managing delirium in critically ill patients.

Tectonics and seismicity of the Gulf of Aden: Contributions of edge detection filters applied to potential field data

Several studies have applied edge detection filters based on potential field derivatives, ratios and statistical-based tools to evaluate structures and provide interpretations. These edge filters provide different responses that may lead to false interpretations, making the selection of an effective filter that can provide optimum response difficult for users. Evaluating the reliability of the edge filters and avoiding false interpretations of the geologic structures requires simultaneous evaluation of filters applied to the same set of theoretical models. By using 2.5D models of gravity and magnetic synthetic data, we evaluate the performance of 21 edge detection filters based on different scenarios. The outcome of the various tests shows that filters of the third class give best results, with reference to the second and first class, and present good to moderate resolution in gravity and magnetic models. This comparison provides a means of inferring the tectono-structural styles, having generated multiple results from different filters and screening for artefacts (i.e., false impressions). Thereafter, we applied the edge enhancement filters to the magnetic and free-air gravity data of Aden Rift. Boundaries corresponding to seafloor spreading, divergent plate and transform faults were identified. The boundaries correlate well with the source locations of earthquakes at shallow depths. In addition to the dominant extensional tectonic regime, we suggest that the local fault system influenced by the Afar plume provides insights to the complex interaction between magmatic, sedimentary, and tectonic forces, shaping the geology of the Arabian-Nubian triple junction and contributes to the dynamics of the Gulf of Aden. The occurrence of earthquake activities along normal and transform fault zones which correlates with identified structural boundaries resulting from the application of edge detection filters provides a novel application to the study of rifting processes by multiple observation techniques.

Construction and Observation of Flexibly Controllable High-Dimensional Non-Hermitian Skin Effects.

Non-Hermitian skin effect (NHSE) is one of the most fundamental phenomena in non-Hermitian physics. It is established that 1D NHSE originates from the nontrivial spectral winding topology. However, the topological origin behind the higher-dimensional NHSE remains unclear, which poses a substantial challenge in constructing and manipulating high-dimensional NHSEs. Here, an intuitive bottom-to-top scheme to construct high-dimensional NHSEs is proposed, through assembling multiple independent 1D NHSEs. Not only the elusive high-dimensional NHSEs can be effectively predicted from the well-defined 1D spectral winding topologies, but also the high-dimensional generalized Brillouin zones can be directly synthesized from the 1D counterparts. As examples, two 2D nonreciprocal acoustic metamaterials are experimentally implemented to demonstrate highly controllable multi-polar NHSEs and hybrid skin-topological effects, where the sound fields can be frequency-selectively localized at any desired corners and boundaries. These results offer a practicable strategy for engineering high-dimensional NHSEs, which can boost advanced applications such as selective filters and directional amplifiers.

Fast collective motions of backbone in transmembrane α helices are critical to water transfer of aquaporin.

Fast collective motions are widely present in biomolecules, but their functional relevance remains unclear. Herein, we reveal that fast collective motions of backbone are critical to the water transfer of aquaporin Z (AqpZ) by using solid-state nuclear magnetic resonance (ssNMR) spectroscopy and molecular dynamics (MD) simulations. A total of 212 residue site-specific dipolar order parameters and 158 15N spin relaxation rates of the backbone are measured by combining the 13C- and 1H-detected multidimensional ssNMR spectra. Analysis of these experimental data by theoretic models suggests that the small-amplitude (~10°) collective motions of the transmembrane α helices on the nanosecond-to-microsecond timescales are dominant for the dynamics of AqpZ. The MD simulations demonstrate that these collective motions are critical to the water transfer efficiency of AqpZ by facilitating the opening of the channel and accelerating the water-residue hydrogen bonds renewing in the selectivity filter region.

Mechanistic basis of the dynamic response of TWIK1 ionic selectivity to pH

Highly selective for K+ at neutral pH, the TWIK1 channel becomes permeable to Na+ upon acidification. Using molecular dynamics simulations, we identify a network of residues involved in this unique property. Between the open and closed states previously observed by electron microscopy, molecular dynamics simulations show that the channel undergoes conformational changes between pH 7.5–6 involving residues His122, Glu235, Lys246 and Phe109. A complex network of interactions surrounding the selectivity filter at high pH transforms into a simple set of stronger interactions at low pH. In particular, His122 protonated by acidification moves away from Lys246 and engages in a salt bridge with Glu235. In addition, stacking interactions between Phe109 and His122, which stabilize the selectivity filter in its K+-selective state at high pH, disappear upon acidification. This leads to dissociation of the Phe109 aromatic side chain from this network, resulting in the Na+-permeable conformation of the channel.