Effect of confinement on water properties in super-hydrophilic pores using MD simulations with the mW model.

CONTEXT: We explore the influence of strongly hydrophilic confinement on various properties of water, such as density, enthalpy, potential energy, radial distribution function, entropy, specific heat capacity, structural dynamics, and transition temperatures (freezing and melting temperatures), using monatomic water (mW) model. The properties of water are found to be dependent on confinement and the wall-fluid surface interaction. Hysteresis loops are observed for density, enthalpy, potential energy, and entropy around the transition temperatures, while the size of hysteresis loops varies with confinement and surface interaction. In smaller pore sizes (H ≤ 20), the solid phase displays a higher density compared to the liquid phase, which is unconventional behavior compared to bulk water systems due to the pronounced hydrophilic properties of the confinement surface. Specific heat capacity exhibits more oscillations in the confined system compared to bulk water, stemming from uneven enthalpy differences across equal temperature intervals. During phase transformation in both heating and quenching processes, there is an abrupt change observed in specific heat capacity. Confinement exerts a notable impact on entropy in the solid phase, but its influence is negligible in the liquid phase. At lower pore sizes (H < 25 Å), there is more fluctuation in freezing temperature for all wall-fluid interactions, which diminishes beyond pore sizes of H > 25 Å. Similarly, more oscillatory behavior is observed in melting temperatures at lower pore sizes (H < 40 Å), which diminishes at higher pore sizes (H > 40 Å). During the quenching process, a sudden jump in the in-plane orientational and tetrahedral order parameters indicates the formation of an ordered phase, specifically a diamond crystalline structure. The percentages of different crystalline structures (cubic diamond, hexagonal diamond, and 2D hexagonal) vary with both the confinement size and the wall-fluid interaction strength. METHODS: Cooling and heating simulations are conducted with the mW water model using LAMMPS for different nanoscale confinement separation sizes ranging from 8.5 to 70 Å within the temperature range of 100-350 K. The water is modeled using two-body and three-body interaction potential (Stillinger-Weber potential) and the confinement is introduced using LJ 9-3 water-wall interaction potential. Entropy is calculated using RDF data obtained from the simulation experiments for each temperature point with increments or decrements of 2.5 K. The transition temperatures are estimated using the specific heat capacity analysis.

Design of insensitive high explosives based on FOX-7: a theoretical prospectives.

CONTEXT: This article presents a theoretical study of three insensitive high explosives based on the FOX-7 moiety. A few heterocyclic five- and six-member nitrogen-rich compounds have been created in an effort to better serve as a potential insensitive high explosive. It has been addressed how these molecules should be optimised in terms of stability, sensitivity, detonation properties, IR frequency computations, formal charge calculations, and more. Comprehensive research has been done on these compounds' molecular density and energy of activation associated with the conversion from nitro (C-NO2) to nitrito (C-ONO) during the initial phase of their decomposition. The bond dissociation energy along with BSSE correction for the most reactive C-NO2 bond is examined. The two designed molecules have intra-molecular hydrogen-bonding while other does not have any intra-molecular hydrogen-bonding. The newly designed compounds exhibit higher detonation values compared to TNT, which suggests that they ought to be prepared in a laboratory by skilled experimenters. METHODS: The stability of the C-NO2 link and the covalent character of the bonds have both been calculated using the atoms in molecule (AIM) method. The electronic structure calculations have been recovered at DFT method with aug-cc-pVDZ basis set using the Gaussian-16 quantum chemistry programme.

Probing the general base for DNA polymerization in telomerase: a molecular dynamics investigation.

Telomerase is an RNA-dependent DNA polymerase that plays a role in the maintenance of the 3' end of the eukaryotic chromosome, known as a telomere, by catalyzing the DNA polymerization reaction in cancer and embryonic stem cells. The detailed molecular details of the DNA polymerization by telomerase, especially the general base for deprotonating the terminal 3'-hydroxyl, which triggers the chemical reaction, remain elusive. We conducted a computational investigation using hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations to probe the detailed mechanism of the reaction. Our simulations started with the telomerase:RNA:DNA:dNTP ternary complex, and by using enhanced sampling QM/MM MD simulations, we probed the general base involved directly in the polymerization. We report the participation of an aspartate (Asp344) coordinated to Mg and an active site water molecule, jointly acting as a base during nucleic acid addition. The Asp344 residue remains transiently protonated during the course of the reaction, and later it deprotonates by transferring its proton to the water at the end of the reaction.

Elucidating the Molecular Basis of Avibactam-Mediated Inhibition of Class†A ß-Lactamases.

Disseminating antibiotic resistance rendered by bacteria against the widely used ß-lactam antibiotics is a serious concern for public health care. The development of inhibitors for drug-resistant ß-lactamase enzymes is vital to combat this rapidly escalating problem. Recently, the U.S. Food and Drug Administration approved a non-ß-lactam inhibitor called avibactam for the treatment of complicated intra-abdominal and urinary tract infections caused by drug-resistant Gram-negative bacteria. This work sheds light on the molecular origin of the inhibitory effect of avibactam against the drug-resistant CTX-M variant of class A ß-lactamases. In particular, we probed the structural evolution, dynamics features, and energetics along the acylation and deacylation reaction pathways through enhanced sampling molecular dynamics methods and free-energy calculations. We scrutinized the roles of active site residues, the nature of the carbamoyl linkage formed in the inhibitor-enzyme covalent intermediate, and other structural features of the inhibitor molecule. By unraveling the reasons behind the inhibition of all the deacylation routes, we can explain various experimental structural and kinetics data, and propose a way to design new inhibitors based on the ß-lactam framework.

Molecular insights into avibactam mediated class C ß-lactamase inhibition: competition between reverse acylation and hydrolysis through desulfation.

Avibactam is one of the promising next generation ß-lactamase inhibitors due to its exceptional inhibition against wide-spectrum serine ß-lactamases. The unusual reversible acylation mechanism has particularly gained interest to explain the inhibition mechanism of avibactam. We explore the mechanism of acylation and deacylation involving avibactam in class-C ß-lactamases (CBLs) through hybrid quantum mechanical/molecular mechanical (QM/MM) enhanced sampling molecular dynamics (MD) simulations. Based on these computations, we probe the kinetic stability of the acyl-enzyme complex formed by avibactam and CBLs, thereby gaining molecular level insights into the avibactam-mediated inhibition of CBLs.

Platelet Indices as a Marker of Severity in Non-diabetic NonHypertensive Acute Ischemic Stroke Patients.

BACKGROUND: Platelet activation & aggregation are critical in pathogenesis of acute ischemic stroke. Mean platelet volume (MPV) & Platelet distribution width (PDW) are markers & determinants of platelet function. Larger platelets are metabolically more active, produce more prothrombotic factors, aggregate more easily & act as index of homeostasis and its dysfunction thrombosis. MATERIAL: We studied 70 non diabetic non hypertensive ischemic stroke patients without previous thrombotic events & not on anti platelet medications within 24 hour of onset of symptoms & compared with equal number of age and sex matched controls. Severity of stroke was calculated by Canadian neurological scale (CNS).Platelet indices were obtained from SYSMEX KX-21. OBSERVATION: Mean age of patients was 55 ± 7.11 and of controls was 52 ± 5.37. According to CNS patients were divided in two groups; with comprehension deficit (1st group, 32 patients) & without comprehension deficit (2nd group, 38 patients).Mean value for PDW & MPV in 1st group was 18.675 ± 3.494 & 12.894 ± 1.270 respectively and in 2nd group was 18.62 ± 3.387 & 12.42 ± 0.984 respectively and was significantly higher than mean value of 15.694 ± 3.127 & 10.46 ± 1.273 of PDW & MPV respectively in controls. In both study groups PDW & MPV was found to be significantly associated with severity of motor deficit. CONCLUSION: In patients of ischemic stroke platelet indices may be used for predicting severity of motor deficit. Although larger sample size and multivariate analysis is required before this can be used regularly in clinical practice.

Hydrolysis of cephalexin and meropenem by New Delhi metallo-ß-lactamase: the substrate protonation mechanism is drug dependent.

Emergence of antibiotic resistance due to New Delhi metallo-ß-lactamase (NDM-1) bacterial enzymes is of great concern due to their ability to hydrolyze a wide range of antibiotics. There are ongoing efforts to obtain the atomistic details of the hydrolysis mechanism in order to develop inhibitors for NDM-1. In particular, it remains elusive how drug molecules of different families of antibiotics are hydrolyzed by NDM-1 in an efficient manner. Here we report the detailed molecular mechanism of NDM-1 catalyzed hydrolysis of cephalexin, a cephalosporin family drug, and meropenem, a carbapenem family drug. This study employs molecular dynamics (MD) simulations using hybrid quantum mechanical/molecular mechanical (QM/MM) methods at the density functional theory (DFT) level, based on which reaction pathways and the associated free energies are obtained. We find that the mechanism and the free energy barrier for the ring-opening step are the same for both the drug molecules, while the subsequent protonation step differs. In particular, we observe that the mechanism of the protonation step depends on the R2 group of the drug molecule. Our simulations show that allylic carbon protonation occurs in the case of the cephalexin drug molecule where Lys211 is the proton donor, and the proton transfer occurs via a water chain formed (only) at the ring-opened intermediate structure. Based on the free energy profiles, the overall kinetics of drug hydrolysis is discussed. Finally, we show that the proposed mechanisms and free energy profiles could explain various experimental observations.

Coexistence of cutaneous tuberculosis (scrofuloderma) and hanseniasis-a rare presentation.

Cutaneous tuberculosis, pulmonary tuberculosis and hanseniasis are all caused by different spp. of Mycobacterium, an intracellular pathogen whose development depends on impaired cell mediated immunity. Scrofuloderma is the most common variant of cutaneous tuberculosis, which is characterized by a direct extension of the skin which overlies the infected lymph gland, bone or joint, that breaks down to form an undermined ulcer. We are reporting a rare association of Scrofuloderma (cutaneous tuberculosis) with Hanseniasis (leprosy) in an adult male whose immune status was controversial.