Isoprenoid glycerol dialkyl glycerol tetraethers (GDGTs), characteristic membrane lipids of archaea, are widely used in ecological and geochemical studies, especially for paleoenvironmental reconstruction. Glycerol monoalkyl glycerol tetraethers (GMGTs, also known as H-GDGTs), a unique variant of GDGTs, have covalent bonds linking the two alkyl chains. Despite some studies suggesting a link between GMGTs and high temperatures, the reliability and mechanisms remain unclear. Using molecular dynamics simulations, we elucidated the mechanism connecting GMGTs to high temperatures. Our findings show that H-bridging linkages reduce the distance between alkyl chains, leading to thicker and denser membranes with lower fluidity and permeability. The diffusion coefficient of GMGTs decreased by approximately 35 % compared to GDGTs, indicating their role as a archaeal high-temperature adaptation. This study provides a mechanistic basis for using archaeal GMGTs in geochemical studies and enhances confidence in their use for paleotemperature reconstruction.

Wet-chemically recovering phosphorus (P) from sewage sludge incineration ash (SSIA) has already become a global initiative to address P deficit, but effectively isolating P from these accompanying metals (AMs) through adsorption in a SSIA-derived extract remains elusive. Here, we devised a hydrothermal stimulus-motivated thermodynamic and kinetic enhancement to gain anionic ethylenediaminetetraacetic acid (EDTA) molecular interfaces for AM enclosure to resolve this conundrum. A new dosage rule based on the EDTA coordination ratio with AMs was established for the first time. Upon hydrothermal extraction at 140 °C for 1 h, the P extraction efficiency reached 96.7% or higher for these obtained SSIA samples, and then exceptional P sequestration from these EDTA-chelated AMs was realized by the peculiar lanthanum (La)-based nanoadsorbent (having 188.86 mg P/g adsorbent at pH ∼ 3.0). Relevant theoretical calculations unraveled that these delocalized electrons of tetravalent EDTA molecules boosted the enclosure of liberated AMs, thereby entailing a substantially increased negative adsorption energy (-408.7 kcal/mol) of P in the form of H2PO4- through intruding lattice-edged carbonates to coordinate La with monodentate mononuclear over LaCO5(1 0 1). This work highlights the prospect of molecular adaptation of these common extractants in wet-chemical P recovery from various P-included wastes, further sustaining global P circularity.

Self-assembling virus-like particles (VLPs) are promising platforms for vaccine development. However, the unpredictability of the physical properties, such as self-assembly capability, hydrophobicity, and overall stability in engineered protein particles fused with antigens, presents substantial challenges in their downstream processing. We envision that these challenges can be addressed by combining more precise computer-aided molecular dynamics (MD) simulations with experimental studies on the modified products, with more to-date forcefield descriptions and larger models closely resembling real assemblies, realized by rapid advancement in computing technology. In this study, three chimeric designs based on the hepatitis B core (HBc) protein as model vaccine candidates were constructed to study and compare the influence of inserted epitopes as well as insertion strategy on HBc modifications. Large partial VLP models containing 17 chains for the HBc chimeric model vaccines were constructed based on the wild-type (wt) HBc assembly template. The findings from our simulation analysis have demonstrated good consistency with experimental results, pertaining to the surface hydrophobicity and overall stability of the chimeric vaccine candidates. Furthermore, the different impact of foreign antigen insertions on the HBc scaffold was investigated through simulations. It was found that separately inserting two epitopes into the HBc platform at the N-terminal and the major immunogenic regions (MIR) yields better results compared to a serial insertion at MIR in terms of protein structural stability. This study substantiates that an MD-guided design approach can facilitate vaccine development and improve its manufacturing efficiency by predicting products with extreme surface hydrophobicity or structural instability.

The nanogap memory (NGM) device, emerging as a promising nonvolatile memory candidate, has attracted increasing attention for its simple structure, nano/atomic scale size, elevated operating speed, and robustness to high temperatures. In this study, nanogap memories based on Pd, Au, and Pt were fabricated by combining nanofabrication with electromigration technology. Subsequent evaluations of the electrical characteristics were conducted under ambient air or vacuum conditions at room temperature. The investigation unveiled persistent challenges associated with metal NGM devices, including (1) prolonged SET operation time in comparison to RESET, (2) the potential generation of error bits when enhancing switching speeds, and (3) susceptibility to degradation during program/erase cycles. While these issues have been encountered by predecessors in NGM device development, the underlying causes have remained elusive. Employing molecular dynamics (MD) simulation, we have, for the first time, unveiled the dynamic processes of NGM devices during both SET and RESET operations. The MD simulation highlights that the adjustment of the tunneling gap spacing in nanogap memory primarily occurs through atomic migration or field evaporation. This dynamic process enables the device to transition between the high-resistance state (HRS) and the low-resistance state (LRS). The identified mechanism provides insight into the origins of the aforementioned challenges. Furthermore, the study proposes an effective method to enhance the endurance of NGM devices based on the elucidated mechanism.

Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.

Mucus penetration is one of the physiologic barriers of inhalation and nanocarriers can effectively facilitate the permeation of drugs. The interactions between the nanocarriers and mucin are crucial for penetration across the mucus layer on the respiratory tract. In this study, we proposed a molecular dynamics (MD) simulation method for the screening of polysaccharides that acted as the surface modification materials for inhalable nano-preparations to facilitate mucus penetration. MD revealed all-atom interactions between the monomers of polysaccharides, including dextran (DEX)/hyaluronic acid (HA)/carboxymethyl chitosan (CMCS) and the human mucin protein MUC5AC (hMUC5AC). The obtained data showed that DEX formed stronger non-covalent bonds with hMUC5AC compared to HA and CMCS, which suggested that HA and CMCS had better mucus permeability than DEX. For the in vitro verification, HA/CMCS-coated liposomes and DEX/PEG-inserted liposomes were prepared. The results of mucin interactions and mucus penetration studies confirmed that HA and CMCS possessed the weakest interactions with mucin and facilitated the mucus penetration, which was in consistent with the data from MD simulation. This work may shed light on the MD simulation-based screening of surface modification materials for inhalable nano-preparations to facilitate mucus penetration.

Chaperonins Hsp60s are required for cellular vitality by assisting protein folding in an ATP-dependent mechanism. Although conserved, the human mitochondrial mHsp60 exhibits molecular characteristics distinct from the E. coli GroEL, with different conformational assembly and higher subunit association dynamics, suggesting a different mechanism. We previously found that the pathological mutant mHsp60V72I exhibits enhanced subunit association stability and ATPase activity. To provide structural explanations for the V72I mutational effects, here we determined a cryo-EM structure of mHsp60V72I. Our structural analysis combined with molecular dynamic simulations showed mHsp60V72I with increased inter-subunit interface, binding free energy, and dissociation force, all contributing to its enhanced subunit association stability. The gate to the nucleotide-binding (NB) site in mHsp60V72I mimicked the open conformation in the nucleotide-bound state with an additional open channel leading to the NB site, both promoting the mutant\'s ATPase activity. Our studies highlight the importance of mHsp60\'s characteristics in its biological function.

Wedelolactone (WEL) is a small molecule compound isolated from Eclipta prostrate L., which has been reported to possess various biological activities such as anti-hepatotoxicity, anti-hypertension, anti-tumour, anti-phospholipase A2 and detoxification activity against snake venom. In the present study, we investigated the interaction of WEL with human serum albumin (HSA) using simultaneous fluorescence, UV-visible spectroscopy, 3D fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), molecular docking technique and molecular dynamics simulation. We found that the interaction between HSA and WEL can exhibit a static fluorescence burst mechanism, and the binding process is essentially spontaneous, with the main forces manifested as hydrogen bonding, van der Waals force and electrostatic interactions. Competitive binding and molecular docking studies showed that WEL preferentially bound to HSA in substructural region IIA (site I); molecular dynamics simulations showed that HSA interacted with WEL to form a stable complex, which also induced conformational changes in HSA. The study of the interaction between WEL and HSA can provide a reference for a more in-depth study of the pharmacodynamic mechanism of WEL and its further development and utilisation.

The most common cause of respiratory tract illness in newborns and young children is the respiratory syncytial virus (RSV). There is no approved vaccination or specific antiviral medication for RSV infections. Here, an attempt has been made to explore the potential of currently marketed drugs as well as their probable derivatives to improve the possibility of developing stronger medications against RSV. From the 100 synthetic drug compounds library, the best drug molecule was identified through drug-likeness properties, toxicity, molecular docking and molecular dynamics simulations. Molecular Mechanics Generalized Born Surface Area (MM-GBSA) was also a method that was applied in this study. Daclatasvir showed the highest binding energy and appeared as the best drug to inhibit matrix protein and a fusion protein of RSV. Based on Daclatasvir, 40 computational derivatives were made. D28, D34 and D40 showed far better results than the actual drug. Changes in lipophilicity character increase the binding energy of derivatives. Molecular dynamic simulations showed their non-deviated, non-fluctuated and stable complex formation with target proteins. The high number of amino acid contacts throughout the trajectory increases the stability and effectiveness of derivatives. The key to producing a novel medicine to eradicate RSV is provided by derivatives. Daclatasvir will be employed as a potential RSV inhibitor up until that point.Communicated by Ramaswamy H. Sarma.

Most of the breast cancers are estrogen receptor-positive recurring with a steady rate of up to 20 years dysregulating the normal cell cycle. Dinaciclib is still in clinical trials and considered as a research drug against such cancers targeting CDK2.The major goal of this study was to identify the potential inhibitors of CDK-2 present in Moringa oleifera for treating hormonal receptor positive breast cancers. For this purpose, in silico techniques; molecular docking, MM-GBSA and molecular dynamics simulations were employed to screen Moringa oleifera compounds and their anticancer potential was determined against CDK-2 protein targets. Among 36 compounds of Moringa oleifera reported in literature, chlorogenic acid (1), quercetin (2), ellagic acid (3), niazirin (4), and kaempferol (5) showed good affinity with the target. The interaction of the compounds was visualized using PYMOL software. The profiles of absorption, distribution, metabolism, excretion (ADME) and toxicity were determined using SWISS and ProTox II webservers. The MTT assay was performed in-vitro using MCF-7 cancer cell lines to validate the anticancer potential of Moringa oleifera leaf extract.MTT assay results revealed no significant change in proliferation of Mcf-7 cells following 24 h treatment with fraction A (petroleum ether). However, significant antiproliferative effect was observed at 200 µg/mL dose of fraction B (ethyl acetate) and cell viability was reduced to 40%.In conclusion, the data suggested that all the compounds with highest negative docking score than the reference could be the potential candidates for cyclin dependent kinase-2 (CDK-2) inhibition while ellagic acid, chlorogenic acid and quercetin being the most stable and potent inhibitors to treat estrogen receptor positive breast cancer targeting CDK-2. Moreover, the data suggested that further investigation is required to determine the optimum dose for significant antiproliferative effects using in-vivo models to validate our findings of in-silico analysis.