Insight into the Mechanism of d-Glucose Accelerated Exchange in GLUT1 from Molecular Dynamics Simulations.

Transmembrane glucose transport, facilitated by glucose transporters (GLUTs), is commonly understood through the simple mobile carrier model (SMCM), which suggests that the central binding site alternates exposure between the inside and outside of the cell, facilitating glucose exchange. An alternative "multisite model" posits that glucose transport is a stochastic diffusion process between ligand-operated gates within the transporter's central channel. This study aims to test these models by conducting atomistic molecular dynamics simulations of multiple glucose molecules docked along the central cleft of GLUT1 at temperatures both above and below the lipid bilayer melting point.

Generation of a Nonbilayer Lipid Nanoenvironment after Epitope Binding Potentiates Neutralizing HIV-1 MPER Antibody.

Establishment of interactions with the envelope lipids is a cardinal feature of broadly neutralizing antibodies (bnAbs) that recognize the Env membrane-proximal external region (MPER) of HIV. The lipid envelope constitutes a relevant component of the full "quinary" MPER epitope, and thus antibodies may be optimized through engineering their capacity to interact with lipids. However, the role of the chemically complex lipid nanoenvironment in the mechanism of MPER molecular recognition and viral neutralization remains poorly understood.

Building predictive Markov models of ion channel permeation from molecular dynamics simulations.

Molecular dynamics (MD) simulation of biological processes has always been a challenging task due to the long timescales of the processes involved and the large amount of output data to handle. Markov state models (MSMs) have been introduced as a powerful tool in this area of research, as they provide a mechanistically comprehensible synthesis of the large amount of MD data and, at the same time, can be used to rapidly estimate experimental properties of biological processes. Herein, we propose a method for building MSMs of ion channel permeation from MD trajectories, which directly evaluates the current flowing through the channel from the model's transition matrix (T), which is crucial for comparing simulations and experimental data.

Insight from atomistic molecular dynamics simulations into the supramolecular assembly of the aldo-keto reductase from Trypanosoma cruzi.

Context: Currently, Chagas disease represents an important public health problem affecting more than 8 million people worldwide. The vector of this disease is the Trypanosoma cruzi (Tc) parasite. Our research specifically focuses on the structure and aggregation states of the enzyme aldo-keto reductase of Tc (TcAKR) reported in this parasite.

BRAZILIAN HERNIA AND ABDOMINAL WALL SOCIETY STATEMENT ON LARGE HIATAL HERNIAS MANAGEMENT.

Large hiatal hernias, besides being more prevalent in the elderly, have a different clinical presentation: less reflux, more mechanical symptoms, and a greater possibility of acute, life-threatening complications such as gastric volvulus, ischemia, and visceral mediastinal perforation. Thus, surgical indications are distinct from gastroesophageal reflux disease-related sliding hiatal hernias. Heartburn tends to be less intense, while symptoms of chest pain, cough, discomfort, and tiredness are reported more frequently.

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold.

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best.

High-resolution 3-dimensional tomography may be a useful tool for understanding the anatomy of hiatal hernias and surgical planning of patients eligible for laparoscopic or robotic antireflux surgery.

Background: 3D computed tomography (CT) has been seldom used for the evaluation of hiatal hernias (HH) in surgical patients. This study aims to describe the 3D CT findings in candidates for laparoscopic or robotic antireflux surgery or HH repair and compare them with other tests.

Methods: Thirty patients with HH and/or gastroesophageal reflux disease (GERD) who were candidates for surgical treatment and underwent high-resolution CT were recruited.

[Translated article] Trazam project: A mobile application for tracking preparations compounded in a pharmacy department.

Introduction: The primary objective of this study is to describe the design and implementation of a mobile application (App) for tracking preparations compounded in the Pharmacy Department. Secondary objectives include: i) evaluating the time spent on resolving incidents related to the distribution of preparations before and after implementation, ii) assessing users satisfaction with the application, and iii) establishing a panel of quality indicators based on the data extracted from the App.

Methods: 1) Defining application requirements, identifying drugs to be included in the software and outlining different workflows.

N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect.

Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors.

Redox regulation of K7 channels through EF3 hand of calmodulin.

Neuronal K7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B, constituting the calcium responsive domain (CRD).

Early Steps in C-Type Inactivation of the hERG Potassium Channel.

Fast C-type inactivation confers distinctive functional properties to the hERG potassium channel, and its association to inherited and acquired cardiac arrythmias makes the study of the inactivation mechanism of hERG at the atomic detail of paramount importance. At present, two models have been proposed to describe C-type inactivation in K-channels. Experimental data and computational work on the bacterial KcsA channel support the hypothesis that C-type inactivation results from a closure of the selectivity filter that sterically impedes ion conduction.

COMPLICATIONS AND LATE FOLLOW-UP OF SCOPINARO'S SURGERY WITH GASTRIC PRESERVATION: 1570 PATIENTS OPERATED IN 20 YEARS.

Aims: Scopinaro-type biliopancreatic diversion (BPD-S) and its variations are the surgeries that offer the best immediate results in weight loss and regain in the late follow-up. It has a high rate of immediate complications and demands control with frequent laboratory tests. The aim of this study was to analyze the late postoperative complications of 1570 patients operated by biliopancreatic diversion with gastric preservation laparoscopic video with up to 20 years of postoperative follow-up.

A Potential Route of Capsaicin to Its Binding Site in the TRPV1 Ion Channel.

Transient receptor potential (TRP) ion channels are important pharmacological targets because of their role in the perception of pain, and so, understanding their chemical regulation is essential for the development of analgesic drugs. Among the currently known TRP channel chemical agonists, capsaicin, the active compound of chili pepper, is probably the most exhaustively studied. The availability of the three-dimensional structure of the vanilloid receptor 1 (TRPV1) has fueled computational studies revealing the molecular details of capsaicin binding modes.

Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.

Hyaluronic acid (HA), through its interactions with the cluster of differentiation 44 (CD44), acts as a potent modulator of the tumor microenvironment, creating a wide range of extracellular stimuli for tumor growth, angiogenesis, invasion, and metastasis. An innovative antitumor treatment strategy based on the development of a nanodevice for selective release of an inhibitor of the HA-CD44 interaction is presented. Computational analysis was performed to evaluate the interaction of the designed tetrahydroisoquinoline-ketone derivative () with CD44 binding site.

Laparoscopic appendicectomy without the use of disposable materials - a low-cost alternative - 1,552 cases operated in 20 years.

Introduction: Laparoscopic appendectomy does not have a single protocol on its technical systematization, access routes, and use of energy and staplers. The cost of disposable materials can prevent its widespread use. Alternatives to decrease cost can help disseminate the laparoscopic access to appendectomy.

An Integrated Mass Spectrometry and Molecular Dynamics Simulations Approach Reveals the Spatial Organization Impact of Metal-Binding Sites on the Stability of Metal-Depleted Metallothionein-2 Species.

Mammalian metallothioneins (MTs) are a group of cysteine-rich proteins that bind metal ions in two α- and β-domains and represent a major cellular Zn(II)/Cu(I) buffering system in the cell. At cellular free Zn(II) concentrations (10-10 M), MTs do not exist in fully loaded forms with seven Zn(II)-bound ions (ZnMTs). Instead, MTs exist as partially metal-depleted species (ZnMT) because their Zn(II) binding affinities are on the nano- to picomolar range comparable to the concentrations of cellular Zn(II).

Ion Conduction Mechanism as a Fingerprint of Potassium Channels.

K-channels are membrane proteins that regulate the selective conduction of potassium ions across cell membranes. Although the atomic mechanisms of K permeation have been extensively investigated, previous work focused on characterizing the selectivity and occupancy of the binding sites, the role of water molecules in the conduction process, or the identification of the minimum energy pathways enabling permeation. Here, we exploit molecular dynamics simulations and the analytical power of Markov state models to perform a comparative study of ion conduction in three distinct channel models.

Multiple Interactions of Glucose with the Extra-Membranous Loops of GLUT1 Aid Transport.

Molecular dynamics simulations amounting to ≈8 μs demonstrate that the glucose transporter GLUT1 undergoes structural fluctuations mediated by the fluidity of the lipid bilayer and the proximity to glucose. The fluctuations of GLUT1 increase as the glucose concentration is raised. These fluctuations are more pronounced when the lipid bilayer is in the fluid compared to the gel phase.

Structure based analysis of K channel with a DEND syndrome mutation in murine skeletal muscle.

Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (K) channel. In addition to diabetes, DEND patients present muscle weakness as one of the symptoms, and although the muscle weakness is considered to originate in the brain, the pathological effects of mutated K channels in skeletal muscle remain elusive. Here, we describe the local effects of the K channel on muscle by expressing the mutation present in the K channels of the DEND syndrome in the murine skeletal muscle cell line C2C12 in combination with computer simulation.

The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules.

Cholesterol is a major component of mammalian plasma membranes that not only affects the physical properties of the lipid bilayer but also is the function of many membrane proteins including G protein-coupled receptors. The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals and in their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator inducing a high-affinity state for orthosteric ligands through a molecular mechanism that has yet to be determined.

Conduction and Gating Properties of the TRAAK Channel from Molecular Dynamics Simulations with Different Force Fields.

In recent years, the K2P family of potassium channels has been the subject of intense research activity. Owing to the complex function and regulation of this family of ion channels, it is common practice to complement experimental findings with the atomistic description provided by computational approaches such as molecular dynamics (MD) simulations, especially, in light of the unprecedented timescales accessible at present. However, despite recent substantial improvements, the accuracy of MD simulations is still undermined by the intrinsic limitations of force fields.

Critical Assessment of Common Force Fields for Molecular Dynamics Simulations of Potassium Channels.

For the last two decades, the KcsA K channel has served as a case study to understand how potassium channels operate at the atomic scale, and molecular dynamics simulations have contributed significantly to the current knowledge of the atomic mechanisms of conduction, inactivation, and gating in this family of membrane proteins. Currently, microsecond trajectories are becoming the new standard in the field, and consequently, it is critical to assess and compare the performance of the classical force fields ordinarily used in simulations of biological systems as well as to quantitatively assess the agreement with experimental data for trajectories of this order of magnitude. To that extent, we performed classical molecular dynamics simulations with CHARMM36 and AMBER-ff14sb force fields using atomic models based on the experimental structure of the KcsA channel in the open/conductive state, at conditions of ionic concentrations and membrane potentials resembling the ones adopted in experiments.

Differential Stability of Aurein 1.2 Pores in Model Membranes of Two Probiotic Strains.

Aurein 1.2 is an antimicrobial peptide from the skin secretion of an Australian frog. In the previous experimental work, we reported a differential action of aurein 1.

Affinity for the Interface Underpins Potency of Antibodies Operating In Membrane Environments.

The contribution of membrane interfacial interactions to recognition of membrane-embedded antigens by antibodies is currently unclear. This report demonstrates the optimization of this type of antibodies via chemical modification of regions near the membrane but not directly involved in the recognition of the epitope. Using the HIV-1 antibody 10E8 as a model, linear and polycyclic synthetic aromatic compounds are introduced at selected sites.

Effect of anionic lipids on ion permeation through the KcsA K-channel.

K-channels are responsible for the efficient and selective conduction of K ions across the plasma membrane. The bacterial K-channel KcsA has historically been used to characterize various aspects of K conduction via computational means. The energetic barriers associated with ion translocation across the KcsA selectivity filter have been computed in various studies, leading to the proposal of two alternate mechanisms of conduction, involving or neglecting the presence of water molecules in between the permeating ions.