The crystal structure of NavAb, a bacterial voltage gated Na(+) channel, exhibits a selectivity filter (SF) wider than that of K(+) channels. This new structure provides the opportunity to explore the mechanism of conduction and help rationalize its selectivity for sodium. Recent molecular dynamics (MD) simulations of single- and two-ion permeation processes have revealed that a partially hydrated Na(+) permeates the channel by exploring three SF binding sites while being loosely coupled to other ions and/or water molecules; a finding that differs significantly from the behavior of K(+) selective channels. Herein, we present results derived from a combination of metadynamics and voltage-biased MD simulations that throws more light on the nature of the Na(+) conduction mechanism. Conduction under 0 mV bias explores several distinct pathways involving the binding of two ions to three possible SF sites. While these pathways are very similar to those observed in the presence of a negative potential (inward conduction), a completely different mechanism operates for outward conduction at positive potentials.
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ongoing coronavirus disease 2019 (COVID-19) pandemic underscores the need for new treatments. Here, we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α ribonuclease endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against current use of non-medical formulations as a preventative or treatment therapy.
Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states. Within this scenario, looking for new developments in the field, we investigate the concentration-dependent binding of ligands to multiple saturable sites in membrane proteins. The study relying on docking and free-energy perturbation provides us with an extensive description of the probability density of protein-ligand states that allows for computation of thermodynamic properties of interest. It also provides one- and three-dimensional spatial descriptions for the ligand density across the protein-membrane system which can be of interest for structural purposes. Illustration and discussion of the results are shown for binding of the general anesthetic sevoflurane against Kv1.2, a mammalian ion channel for which experimental data are available.
The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein’s well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free-energy perturbation of all potential binding sites revealed by the latter, and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of site and conformation-dependent modes of action involving distinct binding sites that increase channel open-probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel-anesthetic interaction, the result is revealing as it demonstrates the process of multiple anesthetic binding events alone may account for open-probability shifts recorded in measurements.
Because of their remarkable roles in electrical cell signaling, voltage-gated cation channels (VGCCs) have been the subject of intense investigations and debate for more than 50 years. Ultimately, the prospective implications of such studies have an impact on our understanding of the molecular properties of VGCCs involved in consciousness, anesthesia, and diseases, to mention a few. The following review aims to summarize our current knowledge of activation of VGCCs by highlighting major methodological innovations in the field and the breakthroughs they allowed. Focusing mainly on insights gained through computer simulations, while acknowledging important experimental findings, we hope to inspire experimentalists to benefit from these approaches in the generation of hypotheses and design of experiments. Also, we outline major future challenges for the field, such as channel modulation, lesser-known receptors, and molecular origins of channel dysfunctions.
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