Computational insight into the effect of alkyl chain length in tetraalkylammonium-based deep eutectic solvents.

The effect of the increase in the alkyl chain length of cation on the properties of deep eutectic solvents based on ethylene glycol has been investigated employing classical molecular dynamics simulations. The change in the structural and dynamic properties in both the bulk and liquid-vapor interface is explored through various analyses. The interaction between the anion and the ethylene glycol increases with an increase in the alkyl chain length of the cation, as observed in the increase of the lifetime of the hydrogen bond formed between the two. The terminal carbon atoms are found to be closer to each other when the cation changes from tetraethylammonium to tetrabutylammonium. The cations are located closer to the interface, and the association of the alkyl chains becomes more significant with increased alkyl chain length, decreasing the surface tension values.

Effect of electronegative atoms on π - π stacking and hydrogen bonding behavior in simple aromatic molecules - An Ab initio MD study.

Ab initio molecular dynamics studies have been performed on fluorobenzene, phenol, and aniline, which have the three most electronegative atoms, fluorine, oxygen, and nitrogen, respectively. Radial distribution functions show strong hydrogen bonding in the phenolic -OH group, whereas it is less prominent in the -NH2 group of aniline. Fluorobenzene does not show strong hydrogen bonds as no solvation shell is found between the fluorine atom and different aromatic hydrogens of the molecule. Spatial distribution functions show that the nitrogen atom of aniline interacts with the aromatic plane, the oxygen atom of phenol is concentrated near the -OH group and fluorobenzene's fluorine atom interacts with the para hydrogen. Liquid phase dimer structures of these systems reveal that perpendicular orientation (Y-shaped) is preferred over parallel ones. Almost half of the total dimer population tends to prefer 90∘±30° angle. H-bond analyses show that fluorobenzene has the longest mean H-bond lifetime for the H-bond between the aromatic hydrogens and the fluorine atoms, whereas the aniline has the least. The mean lifetime between aromatic hydrogens and electronegative atoms increases steadily from aniline to fluorobenzene. Phenolic -OH and amino -NH2 groups show considerably longer mean H-bond lifetime than the aromatic hydrogens. Gas-phase binding energies obtained from quantum chemical calculations show that aniline and phenol dimers have higher binding energy values than the fluorobenzene dimer. Only the phenol dimer shows a perpendicular structure as a stable one, while aniline and fluorobenzene prefer the parallel orientation.

Deciphering the Role of Anions of Ionic Liquids in Modulating the Structure and Stability of ct-DNA in Aqueous Solutions.

Stabilizing biomolecules under ambient conditions can be extremely beneficial for various biological applications. In this context, the utilization of ionic liquids (ILs) in enhancing the stability and preservation of nucleic acids in aqueous solutions is found to be promising. While the role of the cationic moiety of ILs in the said event has been thoroughly explored, the importance of the anionic moiety in ILs, if any, is rather poorly understood. Herein, we examine the function of anions of ILs in nucleic acid stabilization by examining the stability and structure of calf thymus-DNA (ct-DNA) in the presence of various ILs composed of a common 1-ethyl-3-methylimidazolium cations (Emim+) and different anions, which includes Cl-, Br-, NO3-, Ac-,HSO4-and BF4- by employing various spectroscopic techniques as well as Molecular Dynamics (MD) simulation studies. Analysis of our data suggests that the chemical nature of anions including polarity, basicity, and hydrophilicity become an important factor in the overall DNA-IL interaction event. At lower concentrations, the interplay of intermolecular interaction between the IL anions with their respective cations and the solvent molecules becomes a very crucial factor in inducing their stabilizing effect on ct-DNA. However, at higher concentrations of ILs, the ct-DNA stabilization is additionally governed by specific-ion effect. MD simulation studies have also provided valuable insights into molecular-level understanding of the DNA-IL interaction event. Overall, the present study clearly demonstrated that along with the cationic moiety of ILs, the anions of ILs can play a significant role in deciding the stability of duplex DNA in aqueous solution. The findings of this study are expected to enhance our knowledge on understanding of IL-DNA interactions in a better manner and will be helpful in designing optimized IL systems for nucleic acid based applications.

Interaction of the tau fibrils with the neuronal membrane.

Tau proteins are recently gaining a lot of interest due to their active role in causing a range of tauopathies. Molecular mechanisms underlying the tau interaction with the neuronal membrane are hitherto unknown and difficult to characterize using experimental methods. Using the cryo-EM structure of the tau-fibrils we have used atomistic molecular dynamics simulation to model the tau fibril and neuronal membrane interaction using explicit solvation. The dynamics and structural characteristics of the tau fibril with the neuronal membrane are compared to the tau fibril in the aqueous phase to corroborate the effect of the neuronal membrane in the tau structure. Tau fibrils have been modelled using CHARMM-36m force field and the six component neuronal membrane composition is taken from the earlier simulation results. The timescale conceivable in our molecular dynamics simulations is of the order of microseconds which captures the onset of the interaction of the tau fibrils with the neuronal membrane. This interaction is found to impact the tau pathogenesis that finally causes neuronal toxicity. Our study initiates the understanding of tau conformational ensemble in the presence of neuronal membrane and sheds the light on the significant tau-membrane interactions.

Understanding the screening effect of aqueous DES on the IDPs: A molecular dynamics simulation study using amyloid ß42 monomer.

Deep eutectic solvents (DESs) have emerged as the promising replacement to the ionic liquids in solvent engineering for bio-compatibility. We aim to understand the effect of aqueous deep eutectic solvents on the conformation of intrinsically disordered proteins (IDPs). In this context, we have studied the effect on amyloid beta (Aß42) monomer in the hydrated DES composed of tetrabutylammonium chloride and ethylene glycol in a 3:1 ratio using all-atom molecular dynamics simulations. DES is found to effectively screen the interaction of four zones of the amyloid beta monomer with water. Water molecules and the DES constituents modulate the local protein-solvent interactions, in the solvation shell of the protein. In addition, the aqueous DES medium conserves the secondary structure of the Aß42 monomer by increasing the intramolecular hydrogen bonding and D23-K28 salt-bridge interactions when compared to the pure water medium. The current study provides insights into the impact of DES in stabilizing an IDP, at molecular level. We envisage the hindered aggregation of the amyloid beta structures in DES medium over the pure water medium due to the screening of hydrophobic intramolecular interactions.

Vaccination saves lives: a real-time study of patients with chronic diseases and severe COVID-19 infection.

OBJECTIVES: This study aims to describe the demographic and clinical profile and ascertain the determinants of outcome among hospitalized coronavirus disease 2019 (COVID-19) adult patients enrolled in the National Clinical Registry for COVID-19 (NCRC). METHODS: NCRC is an on-going data collection platform operational in 42 hospitals across India. Data of hospitalized COVID-19 patients enrolled in NCRC between 1st September 2020 to 26th October 2021 were examined. RESULTS: Analysis of 29 509 hospitalized, adult COVID-19 patients [mean (SD) age: 51.1 (16.2) year; male: 18 752 (63.6%)] showed that 15 678 (53.1%) had at least one comorbidity. Among 25 715 (87.1%) symptomatic patients, fever was the commonest symptom (72.3%) followed by shortness of breath (48.9%) and dry cough (45.5%). In-hospital mortality was 14.5% (n = 3957). Adjusted odds of dying were significantly higher in age group ≥60 years, males, with diabetes, chronic kidney diseases, chronic liver disease, malignancy and tuberculosis, presenting with dyspnoea and neurological symptoms. WHO ordinal scale 4 or above at admission carried the highest odds of dying [5.6 (95% CI: 4.6-7.0)]. Patients receiving one [OR: 0.5 (95% CI: 0.4-0.7)] or two doses of anti-SARS CoV-2 vaccine [OR: 0.4 (95% CI: 0.3-0.7)] were protected from in-hospital mortality. CONCLUSIONS: WHO ordinal scale at admission is the most important independent predictor for in-hospital death in COVID-19 patients. Anti-SARS-CoV2 vaccination provides significant protection against mortality.

Understanding the conformational changes in the influenza B M2 ion channel at various protonation states.

The characterization of influenza (A/B M2) ion channels is very important as they are potential binding sites for the drugs. We report the all-atom molecular dynamics study of the influenza B M2 ion channel in the presence of explicit solvent and lipid bilayers using the high resolution solid-state NMR structures. The importance of the various protonation states of histidine in the activation of the ion channel is discussed. The conformational changes at the closed and the open structures clearly show that the increase in tilt angle is necessary for the activation of the ion channel. Additionally, the free energy surfaces of the eight systems show the importance of the protonation state of the histidine residues in the activation of the influenza B M2 ion channel. The protonation of the histidine residues increases the tilt angle and the intra-helix distance which is evident from the superimposition of the structures corresponding to the maxima and the minima in the free energy landscape. The findings imply differences in the singly protonated and double protonated conformational states of BM2 ion channel and provide insights to help further studies of these ion channels as the drug targets for the influenza virus.

The effect of lipid composition on the dynamics of tau fibrils.

Knowledge of the interaction of the tau fibrils with the cell membrane is critical for the understanding of the underlying tauopathy pathogenesis. Lipid composition is found to affect the conformational ensemble of the tau fibrils. Using coarse-grained and all-atom molecular dynamics simulations we have shown the effect of the lipid composition in modulating the tau structure and dynamics. Molecular dynamics simulations show that tau proteins interact differentially with the zwitterionic compared to the charged lipid membranes. The negatively charged POPG lipid membranes increase the binding propensity of the tau fibrils. The addition of cholesterol is also found to modify the tau binding to the membrane. The binding of tau fibril leads to the concomitant loss of the ß-sheet structures across the tau residues alongside the change in the membrane properties (like area per lipid, bilayer thickness, and order parameter of the lipid tails) over the pure bilayers.

Molecular dynamics investigation of non-ionic deep eutectic solvents.

All-atom molecular dynamics simulations have been employed to study deep eutectic solvents (DESs) consisting of thymol or naphthol as hydrogen bond donor (HBD) and menthol as hydrogen bond acceptor (HBA). Radial and spatial distribution functions demonstrate the presence of specific interactions between the components in both systems. The highest percentage of strong H-bond was found in the pair having the phenolic systems as HBD and menthol as HBA. The number of hydrogen bonds formed between various components decreases with an increase in temperature. Self diffusivity of the non-ionic DESs is higher than that of ionic DESs. Liquid - vapor interfaces of all the systems are enriched with HBAs.

Helix-coil transition and conformational deformity in Aß42-monomer: a case study using the Zn2+ cation.

The metal ions (like Fe2+, Zn2+, Cu2+) are known to influence the amyloid beta (Aß) aggregation. In this study, we have examined the conformational and dynamical changes during the coordination of Aß-monomer with the Zn2+ ion using all-atom molecular dynamics (MD) simulations using explicit solvent models. We have probed the unfolding of the full-length Aß42 monomer both inclusive and exclusive of the Zn2+ cation, with 1:1 ratio of the peptide and the Zn2+ cation. The inclusion of the Zn2+ cation shows differential intra-peptide interactions which has been probed using various analyses. The Helix - Coil transition of the wild type Aß42 monomer is studied using the steered molecular dynamics simulations by taking the end-to-end C-α distance across the peptide. This gives an idea of the unequal intra - peptide and peptide - water interactions being found across the length of the Aß monomer. The transition of an α-helix dominated wild-type (WT) Aß structure to the unfolded coil structure gives significant evidence of the intra-peptide hydrogen bonding shifts in the presence of the Zn2+ cation. This accounts for the structural and the dynamical variations that take place in the Aß monomer in the presence of the Zn2+ cation to mimic the conditions/environment at the onset of fibrillation.Communicated by Ramaswamy H. Sarma.

The effect of external salts on the aggregation of the multiheaded surfactants: All-atom molecular dynamics studies.

Tailoring the molecular design of the surfactants leads to changes in the aggregation properties. The role of external salts on the aggregation properties of the multiheaded surfactants is investigated using molecular dynamics simulations. The multiheaded surfactants show differential aggregation properties on addition of external salts, as reported earlier from experimental studies. We have modelled the multiheaded surfactants to study the effect of external salts (potassium bromide and sodium salicylate) at three different concentrations using the all-atom modelling and explicit solvation. The influence of external salts on the hydration and aggregation propensity, hydrogen bonding, and the structural characteristics of the surfactant aggregates are probed using various analyses across the four groups of multiheaded surfactants. The larger salicylate ion masks the repulsion between the cationic head groups and acts as an effective promoter of aggregation.

Exploring the candidates for a new protein folding - cross-α amyloid - in available protein databases.

Amyloid fibrils are formed from the assembly of soluble proteins and are responsible for many diseases. They are known to have a cross-ß structure, where the fibril runs perpendicular to the ß-sheets. A new type of tertiary structure formed by the aggregation of peptides in their α-helical form, in naturally occurring as well as synthetic peptides, termed cross-α amyloid has been reported recently. We have studied the interactions responsible for the formation of these cross-α amyloids and proposed a model to determine the peptides that could form these structures. Eight such peptides obtained using the model have been shown to form a cross-α structure using molecular dynamics simulations. The formation of a cross-α structure from eight copies of a randomly chosen peptide and its stability over a microsecond simulation have been demonstrated. A software named Cross-Alpha-Det has been developed that can determine whether a protein can form a cross-α structure from its secondary structure.

Aqueous solutions of hydroxyl-functionalized ionic liquids: Molecular dynamics studies.

A series of aqueous solutions of 1-(n-hydroxyalkyl)-3-(n-hydroxyalkyl) imidazolium bromide ([HOCnCmOHIm][Br], with n and m = 2, 6,10 and 14) were studied by atomistic molecular dynamics simulations. Structural properties were characterized by the radial distribution functions between different pairs, angular distributions and aggregation numbers. Dynamics of the system has been investigated by computing the diffusion of the ions and molecules. Structures of the aggregates formed depend upon the length of the hydroxyalkyl chains. The long-distance spatial correlations observed in solutions with cations having long chain substituent are arising due to the formation of intercalated structures. A thin film like structure is formed in solutions having longer hydroxyalkyl chains, with the structure stabilized by the dispersion interactions between the interdigitated alkyl chains and the hydrogen bond formation between the hydroxyl group of a cation with head group of a different cation. Anions are dispersed near the surface of the film.

Building Capacity for Evidence-Informed Priority Setting in the Indian Health System: An International Collaborative Experience.

India's rapid economic growth has been accompanied by slower improvements in population health. Given the need to reconcile the ambitious goal of achieving Universal Coverage with limited resources, a robust priority-setting mechanism is required to ensure that the right trade-offs are made and the impact on health is maximised. Health Technology Assessment (HTA) is endorsed by the World Health Assembly as the gold standard approach to synthesizing evidence systematically for evidence-informed priority setting (EIPS). India is formally committed to institutionalising HTA as an integral component of the EIPS process. The effective conduct and uptake of HTA depends on a well-functioning ecosystem of stakeholders adept at commissioning and generating policy-relevant HTA research, developing and utilising rigorous technical, transparent, and inclusive methods and processes, and a strong multisectoral and transnational appetite for the use of evidence to inform policy. These all require myriad complex and complementary capacities to be built at each level of the health system . In this paper we describe how a framework for targeted and locally-tailored capacity building for EIPS, and specifically HTA, was collaboratively developed and implemented by an international network of priority-setting expertise, and the Government of India.

Self-Assembly of Cations in Aqueous Solutions of Multiheaded Cationic Surfactants: All Atom Molecular Dynamics Simulation Studies.

Self-assembly of multiheaded surfactants in aqueous solutions has been investigated using atomistic molecular dynamics simulations. The model multiheaded surfactants contain multiple head groups ranging from one to four for a single tail group. Increase in the number of charged head groups has substantial consequences in the aggregation properties of surfactants in their aqueous solutions. Polydisperse aggregates of surfactants are formed in the aqueous solution. The shape and size of the aggregates are dictated by the number of charged head groups present in the surfactant. Our simulations demonstrate that with the increase in the number of charged head groups on the surfactants, the aggregation number decreases, which corroborates previous experimental and theoretical studies. Though experimental studies on the surfactant with four head groups is yet to be performed, we have included the surfactant having four head groups in our studies and compared the results with previous coarse-grained computational study involving four head groups.

Clinical and angiographic profiles and six months outcomes of smokers with acute ST segment elevation myocardial infarction undergoing primary percutaneous coronary angioplasty.

BACKGROUND: Outcomes of primary percutaneous coronary intervention (PCI) for acute STEMI (ST-segment elevation myocardial infarction) in smokers are expected to be better than non-smokers as for patients of acute STEMI with or without fibrinolytic therapy. OBJECTIVES: This comparative study was designed to evaluate the outcomes of primary PCI in patients with acute STEMI in smokers and non-smokers. Clinical and angiographic profile of the two groups was also compared. METHODS: Over duration of two year, a total of 150 consecutive patients of acute STEMI eligible for primary PCI were enrolled and constituted the two groups [Smokers (n=90), Non-smokers (n=60)] of the study population. There was no difference in procedure in two groups. RESULTS: In the present study of acute STEMI, current smokers were about a decade younger than non-smokers (p value=0.0002), majority were male (98.9% vs 56.6%) were male with a higher prevalence of hypertension and diabetes mellitus (61.67% vs 32.28% and 46.67% vs 14.44%, p=0.001) respectively. Smokers tended to have higher thrombus burden (p=0.06) but less multi vessel disease (p=0.028). Thirty day and six month mortality was non-significantly higher in smokers 4.66% vs 1.33% (p=0.261) and 5.33% vs 2.66% (p=NS) respectively. Rate of quitting smoking among smokers was 80.90% at 6 months. CONCLUSION: The study documents that smokers with acute STEMI have similar outcomes as compared to non smokers with higher thrombus burden and lesser non culprit artery involvement. Smokers present at much younger age emphasizing the role of smoking cessation for prevention of myocardial infarction.

Solvation of Methyl Lactate in Water: Molecular Dynamics Studies.

Methyl lactate (ML), a chiral α-hydroxy ester, has been probed widely to understand the competition between two types of intramolecular H-bonds in solvents of different polarities. Recent experimental and high-level quantum chemical studies have revealed the predominant existence of ML-water insertion complexes over addition complexes in aqueous solution. Although the stability of monohydrate insertion conformer was studied accurately, ab initio quantum chemical calculations failed to predict the most stable dihydrate conformer in analogy with the experimental spectroscopic search. Atomistic molecular dynamics simulations of aqueous solution of methyl lactate predict that the population and lifetime of different H-bonded ML-water addition complexes are dictated by their interaction energies. Although the population of dihydrate insertion complexes is higher than that of the monohydrate complexes, the lifetime of the former is smaller than the latter, which is in good agreement with the experimental result. The nature of intramolecular H-bonds within a methyl lactate molecule in aqueous solution is opposite to that in the gas phase due to the solvation process in water by intermolecular H-bonding interactions.

Self-Assembly of Cations in Aqueous Solutions of Hydroxyl-Functionalized Ionic Liquids: Molecular Dynamics Studies.

The effect of presence of a hydroxyl-functionalized alkyl chain of varying carbon number on the self-assembly of cations in aqueous solutions of 1-(n-hydroxyalkyl)-3-decylimidazolium bromide (where the alkyl groups are ethyl, butyl, heptyl, and decyl) has been studied using atomistic molecular dynamics simulations. Spontaneous self-assembly of cations to form aggregates with hydrophobic core and hydrophilic surface is observed. The shape of the aggregates changes from quasispherical in the case of cations with hydroxyheptyl or smaller substituent chain, to a thin film like intercalated aggregate in the case of cations with hydroxydecyl chain. Cations with hydroxydecyl substituent chain exhibit long-range spatial correlations, and the anions are associated with cations to a greater extent due to the higher surface charge density of the aggregate. The ordered film like aggregate is stabilized by the dispersion interactions between the intercalated substituent chains and the intermolecular hydrogen bonds formed between the alkoxy oxygen atoms and the hydrogen atoms of the imidazolium ring. The cations form less compact aggregates with lower aggregation number than their nonhydroxyl analogues in the corresponding aqueous solutions. The intracationic and aggregate structures are governed by the length of the hydroxyalkyl chain.

Segregation of ions at the interface: molecular dynamics studies of the bulk and liquid-vapor interface structure of equimolar binary mixtures of ionic liquids.

The structures of three different equimolar binary ionic liquid mixtures and their liquid-vapor interface have been studied using atomistic molecular dynamics simulations. Two of these binary mixtures were composed of a common cation 1-n-butyl-3-methylimidazolium and varying anions (chloride and hexafluorophosphate in one of the mixtures and chloride and trifluoromethanesulfonate in the other) and the third binary mixture was composed of a common anion, trifluoromethanesulfonate and two imidazolium cations with ethyl and octyl side chains. Binary mixtures with common cations are found to be homogeneous. The anions are preferentially located near the ring hydrogen atoms due to H-bonding interactions. Segregation of ions is observed at the interface with an enrichment of the liquid-vapor interface layer by longer alkyl chains and bigger anions with a distributed charge. The surface composition is drastically different from that of the bulk composition, with the longer alkyl tail groups and bigger anions populating the outermost layer of the interface. The longer alkyl chains of the cations and trifluoromethanesulfonate anions with a smaller charge density show orientational ordering at the liquid-vapor interface.