Unbound Energy Research Articles

Tuning the lanthanide binding tags for preferential actinide chelation: an all atom molecular dynamics study.

The present study focuses on designing mutant peptides derived from the lanthanide binding tag (LBT) to enhance selectivity for trivalent actinide (An3+) ions over lanthanide (Ln3+) metal ions (M). The LBT is a short peptide consisting of only 17 amino acids, and is known for its high affinity towards Ln3+. LBT was modified by substituting hard-donor ligands like asparagine (ASN or N) and aspartic acid (ASP or D) with softer ligand cysteine (CYS or C) to create four mutant peptides: M-LBT (wild-type), M-N103C, M-D105C, and M-N103C-D105C. All atom molecular dynamics (MD) simulations were employed to analyze the binding dynamics and affinities of these mutants with Eu3+ and Am3+ as representatives for trivalent Ln and An ions, respectively. Hydrogen bond dynamics and short-range Coulomb interactions are evaluated from the equilibrium run for all the systems. The study utilized an enhanced sampling method, namely, well-tempered meta-dynamics (WT-MtD), to overcome sampling challenges and obtain converged free energy profiles for the metal-binding interactions. Our simulations studies indicate that both single and double mutations alter the coordination environment within the peptide's binding pocket, potentially increasing Am3+ selectivity over the Eu3+ ion. The binding of Eu3+ and Am3+ to LBT systems was analyzed, showing an unbinding energy barrier of ∼60 kJ mol-1 for the wild-type. The N103C variant increases the binding strength with a barrier over 100 kJ mol-1, while D105C shows a preference for Am3+ with a barrier around 70 kJ mol-1. The doubly mutated N103C-D105C variant favors Am3+ by more than 20 kJ mol-1. The findings suggest N103C for general chelation and N103C-D105C for preferential trivalent Ln/An separation. These insights contribute to the development of more effective and selective chelating agents for preferential actinide binding.

Structure and Energetics of PET-Hydrolyzing Enzyme Complexes: A Systematic Comparison from Molecular Dynamics Simulations.

Discovered in 2016, the enzyme PETase, secreted by bacterial Ideonella Sakaiensis 201-F6, has an excellent hydrolytic activity toward poly(ethylene terephthalate) (PET) at room temperature, while it decreases at higher temperatures due to the low thermostability. Many variants have been engineered to overcome this limitation, which hinders industrial application. In this work, we systematically compare PETase wild-type (WT) and four mutants (DuraPETase, ThermoPETase, FastPETase, and HotPETase) using standard molecular dynamics (MD) simulations and unbinding free energy calculations. In particular, we analyze the enzymes' structural characteristics and binding to a tetrameric PET chain (PET4) under two temperature conditions: T1─300 K and T2─350 K. Our results indicate that (i) PET4 forms stable complexes with the five enzymes at room temperature (∼300 K) and (ii) most of the interactions are localized close to the active site of the protein, where the W185 and Y87 residues interact with the aromatic rings of the substrate. Specifically, (iii) the W185 side-chain explores different conformations in each variant (a phenomenon known in the literature as "W185 wobbling"). This suggests that the binding pocket retains structural plasticity and flexibility among the variants, facilitating substrate recognition and localization events at moderate temperatures. Moreover, (iv) PET4 establishes aromatic interactions with the catalytic H237 residue, stabilizing the catalytic triad composed of residues S160-H237-D206, and helping the system achieve an effective configuration for the hydrolysis reaction. Conversely, (v) the binding affinity decreases at a higher temperature (∼350 K), retaining moderate interactions only for HotPETase. Finally, (vi) MD simulations of complexes formed with poly(ethylene-2,5-furan dicarboxylate) (PEF) show no persistent interactions, suggesting that these enzymes are not yet optimized for binding this alternative semiaromatic plastic polymer. Our study offers valuable insights into the structural stability of these enzymes and the molecular determinants driving PET binding onto their surfaces, sheds light on the mechanistic steps that precede the onset of hydrolysis, and provides a foundation for future enzyme optimization.

Understanding the Multifaceted Mechanism of Compound I Formation in Unspecific Peroxygenases through Multiscale Simulations.

Unspecific peroxygenases (UPOs) can selectively oxyfunctionalize unactivated hydrocarbons by using peroxides under mild conditions. They circumvent the oxygen dilemma faced by cytochrome P450s and exhibit greater stability than the latter. As such, they hold great potential for industrial applications. A thorough understanding of their catalysis is needed to improve their catalytic performance. However, it remains elusive how UPOs effectively convert peroxide to Compound I (CpdI), the principal oxidizing intermediate in the catalytic cycle. Previous computational studies of this process primarily focused on heme peroxidases and P450s, which have significant differences in the active site from UPOs. Additionally, the roles of peroxide unbinding in the kinetics of CpdI formation, which is essential for interpreting existing experiments, have been understudied. Moreover, there has been a lack of free energy characterizations with explicit sampling of protein and hydration dynamics, which is critical for understanding the thermodynamics of the proton transport (PT) events involved in CpdI formation. To bridge these gaps, we employed multiscale simulations to comprehensively characterize the CpdI formation in wild-type UPO from Agrocybe aegerita (AaeUPO). Extensive free energy and potential energy calculations were performed in a quantum mechanics/molecular mechanics setting. Our results indicate that substrate-binding dehydrates the active site, impeding the PT from H2O2 to a nearby catalytic base (Glu196). Furthermore, the PT is coupled with considerable hydrogen bond network rearrangements near the active site, facilitating subsequent O-O bond cleavage. Finally, large unbinding free energy barriers kinetically stabilize H2O2 at the active site. These findings reveal a delicate balance among PT, hydration dynamics, hydrogen bond rearrangement, and cosubstrate unbinding, which collectively enable efficient CpdI formation. Our simulation results are consistent with kinetic measurements and offer new insights into the CpdI formation mechanism at atomic-level details, which can potentially aid the design of next-generation biocatalysts for sustainable chemical transformations of feedstocks.

Design of Novel Coumarin Derivatives as NUDT5 Antagonists That Act by Restricting ATP Synthesis in Breast Cancer Cells

Breast cancer, a heterogeneous disease, is among the most frequently diagnosed diseases and is the second leading cause of death due to cancer among women after lung cancer. Phytoactives (plant-based derivatives) and their derivatives are safer than synthetic compounds in combating chemoresistance. In the current work, a template-based design of the coumarin derivative was designed to target the ADP-sugar pyrophosphatase protein. The novel coumarin derivative (2R)-2-((S)-sec-butyl)-5-oxo-4-(2-oxochroman-4-yl)-2,5-dihydro-1H-pyrrol-3-olate was designed. Molecular docking studies provided a docking score of -6.574 kcal/mol and an MM-GBSA value of -29.15 kcal/mol. Molecular dynamics simulation studies were carried out for 500 ns, providing better insights into the interaction. An RMSD change of 2.4 Å proved that there was a stable interaction and that there was no conformational change induced to the receptor. Metadynamics studies were performed to calculate the unbinding energy of the principal compound with NUDT5, which was found to be -75.171 kcal/mol. In vitro validation via a cytotoxicity assay (MTT assay) of the principal compound was carried out with quercetin as a positive control in the MCF7 cell line and with an IC50 value of 55.57 (+/-) 0.7 μg/mL. This work promoted the research of novel natural derivatives to discover their anticancer activity.

Quality over quantity: Sampling high probability rare events with the weighted ensemble algorithm.

The prediction of (un)binding rates and free energies is of great significance to the drug design process. Although many enhanced sampling algorithms and approaches have been developed, there is not yet a reliable workflow to predict these quantities. Previously we have shown that free energies and transition rates can be calculated by directly simulating the binding and unbinding processes with our variant of the WE algorithm "Resampling of Ensembles by Variation Optimization", or "REVO". Here, we calculate binding free energies retrospectively for three SAMPL6 host-guest systems and prospectively for a SAMPL9 system to test a modification of REVO that restricts its cloning behavior in quasi-unbound states. Specifically, trajectories cannot clone if they meet a physical requirement that represents a high likelihood of unbinding, which in the case of this work is a center-of-mass to center-of-mass distance. The overall effect of this change was difficult to predict, as it results in fewer unbinding events each of which with a much higher statistical weight. For all four systems tested, this new strategy produced either more accurate unbinding free energies or more consistent results between simulations than the standard REVO algorithm. This approach is highly flexible, and any feature of interest for a system can be used to determine cloning eligibility. These findings thus constitute an important improvement in the calculation of transition rates and binding free energies with the weighted ensemble method.

Binding Kinetics Toolkit for Analyzing Transient Molecular Conformations and Computing Free Energy Landscapes.

Understanding ligand binding kinetics and thermodynamics, which involves investigating the free, transient, and final complex conformations, is important in fundamental studies and applications for chemical and biomedical systems. Examining the important but transient ligand-protein-bound conformations, in addition to experimentally determined structures, also provides a more accurate estimation for drug efficacy and selectivity. Moreover, obtaining the entire picture of the free energy landscape during ligand binding/unbinding processes is critical in understanding binding mechanisms. Here, we present a Binding Kinetics Toolkit (BKiT) that includes several utilities to analyze trajectories and compute a free energy and kinetics profile. BKiT uses principal component space to generate approximated unbinding or conformational transition coordinates for accurately describing and easily visualizing the molecular motions. We implemented a new partitioning approach to assign indexes along the approximated coordinates that can be used as milestones or microstates. The program can generate input files to run many short classical molecular dynamics simulations and uses milestoning theory to construct the free energy profile and estimate binding residence time. We first validated the method with a host-guest system, aspirin unbinding from β-cyclodextrin, and then applied the protocol to pyrazolourea compounds and cyclin-dependent kinase 8 and cyclin C complexes, a kinase system of pharmacological interest. Overall, our approaches yielded good agreement with published results and suggest ligand design strategies. The computed unbinding free energy landscape also provides a more complete picture of ligand-receptor binding barriers and stable local minima for deepening our understanding of molecular recognition. BKiT is easy to use and has extensible features for future expansion of utilities for postanalysis and calculations.

An economic model of the drives from Friston's free energy perspective.

This paper is focused on the theory of drives, particularly on its economic model, which was an integral part of Freud's original formulation. Freud was aiming to make a link between the psychic energy of drives and the biophysical rules of nature. However, he was not able to develop this model into a comprehensive system linking the body and the mind. The further development of psychoanalytic theory, in various attempts to comprehend the theory of drives, can be described as taking different approaches. Some of them equate drives with bodily impulses, others abandon the economic model, a few stay with Freud's original model. I believe that the Friston notion of free energy and the hierarchical model of the brain allows us to develop this model and to integrate the economic model into some contemporary theories of drives. I argue against those theories equating drives with biological impulses. My arguments are supported by Freud's project itself but also by recent developments within neuro-psychoanalysis describing the process of mentalizing homeostasis, interoceptive signals and relations with caregivers. I argue for those theories which see the drives as psychic forces, which through developmental processes and cathexes acquire aims and objects, and become intertwined with impulses originating internally and externally, such as affect, interoceptive impulses, perception of the external world, and impulses from erotogenic zones in particular. Here, I present my analysis of the compatibility and consistency of free energy and the hierarchical model perspective, and two psychoanalytical traditions of thoughts: French psychoanalysis and the post-Kleinian school of British psychoanalysis. In particular, my analysis focuses on the contemporary Kleinian notion of unconscious phantasies, especially Bronstein's description of their semiotic aspects. Secondly, I look at Segal's view of drives as dialectic forces of adaptation vs. conservatism. Analyzing the French tradition, I focus on Green's perspective on the drives, Lacan's distinction between drives and desire, and Penot's description of the process of subjectivation. I conclude that free energy, as described by Friston, can be seen as a source of the drives' energy and the process of minimizing it is an equivalent of what Freud described as binding the free energy, in which psychic unbound energy acquires distinctive features and becomes bound.

Mycobacterium Time-Series Genome Analysis Identifies AAC2' as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism.

The World Health Organization has put drug resistance in tuberculosis on its list of significant threats, with a critical emphasis on resolving the genetic differences in Mycobacterium tuberculosis. This provides an opportunity for a better understanding of the evolutionary progression leading to anti-microbial resistance. Anti-microbial resistance has a great impact on the economic stability of the global healthcare sector. We performed a timeline genomic analysis from 2003 to 2021 of 578 mycobacterium genomes to understand the pattern underlying genomic variations. Potential drug targets based on functional annotation was subjected to pharmacophore-based screening of FDA-approved phyto-actives. Reaction search, MD simulations, and metadynamics studies were performed. A total of 4,76,063 mutations with a transition/transversion ratio of 0.448 was observed. The top 10 proteins with the least number of mutations were high-confidence drug targets. Aminoglycoside 2′-N-acetyltransferase protein (AAC2′), conferring resistance to aminoglycosides, was shortlisted as a potential drug target based on its function and role in bait drug synergism. Gentamicin-AAC2′ binding pose was used as a pharmacophore template to screen 10,570 phyto-actives. A total of 66 potential hits were docked to obtain naloxone as a lead—active with a docking score of −6.317. Naloxone is an FDA-approved drug that rapidly reverses opioid overdose. This is a classic case of a repurposed phyto-active. Naloxone consists of an amine group, but the addition of the acetyl group is unfavorable, with a reaction energy of 612.248 kcal/mol. With gentamicin as a positive control, molecular dynamic simulation studies were performed for 200 ns to check the stability of binding. Metadynamics-based studies were carried out to compare unbinding energy with gentamicin. The unbinding energies were found to be −68 and −74 kcal/mol for naloxone and gentamycin, respectively. This study identifies naloxone as a potential drug candidate for a bait drug synergistic approach against Mycobacterium tuberculosis.

Protein aggregation rate depends on mechanical stability of fibrillar structure.

The formation of the fibrillar structure of amyloid proteins/peptides is believed to be associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Since the rate of aggregation can influence neurotoxicity, finding the key factors that control this rate is of paramount importance. It was recently found that the rate of protein aggregation is related to the mechanical stability of the fibrillar structure such that the higher the mechanical stability, the faster the fibril is formed. However, this conclusion was supported by a limited dataset. In this work, we expand the previous study to a larger dataset, including the wild type of Aβ42 peptide and its 20 mutants, the aggregation rate of which was measured experimentally. By using all-atom steered molecular dynamics (SMD) simulations, we can assess the mechanical stability of the fibril structure, which is characterized by the rupture force, pulling work, and unbinding free energy barrier. Our result confirms that mechanical stability is indeed related to the aggregation rate. Since the estimation of the aggregation rate using all-atom simulations is almost forbidden by the current computational capabilities, our result is useful for predicting it based on information obtained from fast SMD simulations for fibrils.

An Anthropocene species of trouble? Negative synergies between earth system change and geological destratification

It is already well understood that unbinding materials and energy from their lithic reservoirs impacts upon Earth systems. But that is just the first stage of a cycle of ‘Anthropocene trouble’. This paper tracks the multiple ways in which subsequent Earth system change reacts back upon the social infrastructures of subsurface exploitation and the landscapes they produce. Shifting fire regimes, intensifying hydrometeorological events and sea level rise impact upon the infrastructures of hydrocarbon extraction, hydroclimatic change impacts upon infrastructures and landscapes of mineral extraction, and both pyroclimatic and hydroclimatic change impact upon nuclear infrastructures and on landscapes already contaminated by radioactive materials. To make sense of these ‘negative synergies’ we draw upon social science diagnoses of late modern hazards as well Anthropocene science’s deepening collaboration between ‘hard rock’ geology and Earth system science.

Is there a trade-off relation between efficiency and power in a collisional Penrose process in an extreme Reissner-Nordström spacetime?

We investigate the power of a collisional Penrose process with an unbound energy extraction from an extreme Reissner-Nordstr\"om black hole. This process takes infinite time in a time coordinate at a constant radial coordinate outside of the black hole. For black holes as a power plant, the power of the process for an observer far away from the black hole can be useful. We define the power as energy gain from the extreme Reissner-Nordstr\"om black hole divided by the time interval of the process in a coordinate time; we estimate the upper bound of the power in a near-horizon limit, while the efficiency of the process can be arbitrary large in that limit. Thus, we conclude that there is no trade-off relation between the efficiency and power in the collisional Penrose process in extreme Reissner-Nordstr\"om spacetime.

Chemical depolymerization of recycled PET to oxadiazole and hydrazone derivatives: Synthesis, characterization, molecular docking and DFT study

The extensive use of polyethylene terephthalate (PET)-based packaging materials has increased the desire to focus on their recycling. In this study, a chemical depolymerization method is proposed for synthesizing terephthalic dihydrazide (TDH) via the aminolysis of post-consumed PET. TDH is further used as a precursor along with 2-chlorobenzoic acid and 4-hydroxybenzoic acid to synthesize aromatic compounds, such as two oxadiazole derivatives, with potential applications. TDH is also used along with 2-chlorobenzaldehyde, benzaldehyde, and 4-hydroxybenzaldehyde to synthesize three hydrazone derivatives. The five compounds (the oxadiazoles and hydrazones) are well characterized by ultraviolet–visible (UV–Vis) spectroscopy, elemental analysis, Fourier-transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR), scanning electron microscopy (SEM), and thermal analysis. The theoretical parameters of the compounds are studied by ab initio density functional theory (DFT). The DFT calculations are conducted at Becke’s three parameter and Lee–Yang–Parr (B3LYP) functional level of calculation with 631-G basis set. Moreover, several thermodynamic parameters at the ground state, such as the point group symmetry, dipole moment, and vibrational frequency, are calculated. The study of molecular docking of the synthesized compounds with target proteins (glucosamine-6-phosphate synthase (GlcN-6-P) and sterol 14α-demethylase (CYP51)) is conducted. Further, different parameters, such as the binding energy (BE), inhibition constant, internal energy, total intermolecular van der Waals forces, unbound energy, and hydrogen bond energy, are calculated. The three of the synthesized compounds are evaluated for antifungal and antibacterial activities using agar well diffusion method. The study of such compounds can offer a good prospective as potential antimicrobial and antifungal leads.

Tension-free Dirac strings and steered magnetic charges in 3D artificial spin ice

3D nano-architectures presents a new paradigm in modern condensed matter physics with numerous applications in photonics, biomedicine, and spintronics. They are promising for the realization of 3D magnetic nano-networks for ultra-fast and low-energy data storage. Frustration in these systems can lead to magnetic charges or magnetic monopoles, which can function as mobile, binary information carriers. However, Dirac strings in 2D artificial spin ices bind magnetic charges, while 3D dipolar counterparts require cryogenic temperatures for their stability. Here, we present a micromagnetic study of a highly frustrated 3D artificial spin ice harboring tension-free Dirac strings with unbound magnetic charges at room temperature. We use micromagnetic simulations to demonstrate that the mobility threshold for magnetic charges is by 2 eV lower than their unbinding energy. By applying global magnetic fields, we steer magnetic charges in a given direction omitting unintended switchings. The introduced system paves the way toward 3D magnetic networks for data transport and storage.

A comprehensive study on retention of selected model substances in β-cyclodextrin-modified high performance liquid chromatography

The quantitative structure-retention relationship (QSRR) models are not only employed in retention behaviour prediction, but also in an in-depth understanding of complex chromatographic systems. The goal of the present research is to enable the comprehensive understanding of retention underlying the separation in β-cyclodextrin (CD) modified reversed-phase high performance liquid chromatography (RP-HPLC) systems, through the development of mixed QSRR models. Moreover, the amount of β-CD adsorbed on the stationary phase surface (β-CDA) is added as the model's input in order to evaluate its contribution to both model performances and retention. Nuclear magnetic resonance (NMR) experiments were conducted to confirm the predicted inclusion complex structures and support the application of in silico tools. The most significant descriptors revealed that retention is governed by the steric factors 7.5 Å distant from the geometrical centre of a molecule, 3D arrangement of atoms determining the molecular size and shape, lipophilicity indicated by topological distances, as well as the unbound system's energy, related to the inclusion complex formation. In addition, a notable effect of the pH of the aqueous phase on the retention of ionizable analytes was shown. In the case of pH of the aqueous phase and β-CDA the change in retention behaviour of the studied analytes was observed only at the highest β-CDA value (5.17 μM/m2), but it was not related to the ionization state of analytes. When the analytes did not change the ionization form across the investigated studied pH range, and the acetonitrile content in the mobile phase was 25% (v/v), the retention factor had low values regardless of the β-CDA; under these circumstances the retention is probably acetonitrile driven.

Binding Trauma

Binding Trauma

Mapping Mechanostable Pulling Geometries of Protein-Ligand Complexes

Anticalin is a non-immunoglobulin protein scaffold with potential as an alternative to monoclonal antibodies for nanoparticle-based drug delivery to cells displaying cytotoxic T-lymphocyte antigen 4 (CTLA-4). In this context, one limiting factor is the resistance of the anticalin:CTLA-4 complex to mechanical forces exerted by fluid shear stress. Here, we used single-molecule AFM force spectroscopy to screen residues along the anticalin backbone and determine the optimal pulling point that achieves maximum mechanical stability of the anticalin:CTLA-4 complex. We used non-canonical amino acid incorporation by amber suppression in the anticalin combined with click chemistry to attach an Fgβ peptide at internal residues of the anticalin. We then used the Fgβ peptide as a handle to mechanically dissociate anticalin from CTLA-4 by applying tension at 8 different anchor residues, and measure the unbinding energy landscape for each pulling geometry. We found that pulling from amino acid position 60 on the anticalin resulted in ∼100% higher mechanical stability of the complex as compared with either the N- or C-terminus. Molecular dynamics (MD) simulations using the coarse-grained Martini force field showed strong agreement with experiments and help explain the mechanisms underlying the geometric dependency of mechanical stability in this therapeutic molecular complex. These results demonstrate that the mechanical stability of receptor-ligand complexes can be optimized by controlling the loading geometry without making any changes to the binding interface.

From Reactive Rainbow to Dynamic Resonance Well.

Scattering resonance is a fascinating phenomenon which manifests as a peak or a dip in an observable as a function of collisional energy (Ec). Its occurrence requires a potential well to support the resonance states. In this regard, reactive resonance is unusual in that it can exist in a reaction with unbound Born-Oppenheimer potential energy surface, on which the quasi-bound states are dynamically trapped-meaning that some energy is temporarily tied to the other degrees of freedom than the reaction coordinate. The concept of vibrational adiabaticity has been the cornerstone in understanding this phenomenon, for which the vibrationally adiabatic well depth is of primary concern. Recent studies on the F + CH3D reaction have accumulated compelling evidence for a dominant resonance-mediated pathway at low Ec as well as for a rainbow feature in pair-correlated angular distribution at higher Ec. Here, we report an in-depth study to not only substantiate both claims but also, more importantly, make the first attempt to quantify the vibrationally adiabatic well depth directly from the observed rainbow structure and then compare with the theoretical prediction.

Enhanced Jarzynski free energy calculations using weighted ensemble.

The free energy of transitions between stable states is the key thermodynamic quantity that governs the relative probabilities of the forward and reverse reactions and the ratio of state probabilities at equilibrium. The binding free energy of a drug and its receptor is of particular interest, as it serves as an optimization function for drug design. Over the years, many computational methods have been developed to calculate binding free energies, and while many of these methods have a long history, issues such as convergence of free energy estimates and the projection of a binding process onto order parameters remain. Over 20 years ago, the Jarzynski equality was derived with the promise to calculate equilibrium free energies by measuring the work applied to short nonequilibrium trajectories. However, these calculations were found to be dominated by trajectories with low applied work that occur with extremely low probability. Here, we examine the combination of weighted ensemble algorithms with the Jarzynski equality. In this combined method, an ensemble of nonequilibrium trajectories are run in parallel, and cloning and merging operations are used to preferentially sample low-work trajectories that dominate the free energy calculations. Two additional methods are also examined: (i) a novel weighted ensemble resampler that samples trajectories directly according to their importance to the work of work and (ii) the diffusion Monte Carlo method using the applied work as the selection potential. We thoroughly examine both the accuracy and efficiency of unbinding free energy calculations for a series of model Lennard-Jones atom pairs with interaction strengths ranging from 2 kcal/mol to 20 kcal/mol. We find that weighted ensemble calculations can more efficiently determine accurate binding free energies, especially for deeper Lennard-Jones well depths.

Harnessing Exciton-Exciton Annihilation in Two-Dimensional Semiconductors.

Strong many-body interactions in two-dimensional (2D) semiconductors give rise to efficient exciton-exciton annihilation (EEA). This process is expected to result in the generation of unbound high energy carriers. Here, we report an unconventional photoresponse of van der Waals heterostructure devices resulting from efficient EEA. Our heterostructures, which consist of monolayer transition metal dichalcogenide (TMD), hexagonal boron nitride (hBN), and few-layer graphene, exhibit photocurrent when photoexcited carriers possess sufficient energy to overcome the high energy barrier of hBN. Interestingly, we find that the device exhibits moderate photocurrent quantum efficiency even when the semiconducting TMD layer is excited at its ground exciton resonance despite the high exciton binding energy and large transport barrier. Using ab initio calculations, we show that EEA yields highly energetic electrons and holes with unevenly distributed energies depending on the scattering condition. Our findings highlight the dominant role of EEA in determining the photoresponse of 2D semiconductor optoelectronic devices.

Targeting galectin-3 by natural glycosides: a computational approach

As a carbohydrate-binding protein, galectin-3 represented as a potential target for numerous therapeutic inventions, as it controls cell proliferation, promotes inflammatory responses, inhibits apoptosis, and a negative regulator of memory formation. The regulations by galectin-3 can be blocked by the compounds having the multivalent presentation of carbohydrate (galactose) derivatives; therefore, the present study focused on the natural glycosides to find a potent inhibitor with reduced toxicity. Here, we introduced a computational pipeline by integrating molecular docking, steered molecular dynamics simulation and molecular dynamics simulation to screen out potential compounds from a library of the natural glycoside. Based on structure mediated virtual screening protocol involving molecular docking and MM-GBSA analysis, four natural glycosides were selected and considered for further induced fit docking (IFD) and steered molecular dynamics simulation approach. According to the docking analysis, all compounds made polar interactions with Glu184, Arg162, His158 and Asn174, while the only spiraeoside showed hydrogen bond with Arg144, a non-conserved residue than other members of galectin family. Interestingly, spiraeoside also showed maximum unbinding energy in steered molecular dynamics simulation which eventually supported the binding free energy analysis by MM-GBSA. Furthermore, the specificity of spiraeoside towards galectin-3 was proved by water–bridge interaction with Arg144 residue in molecular dynamics simulation. Finally, this study highlights the potentiality of natural glycosides as a galectin-3 inhibitor, remarking spiraeoside, which could be a potent inhibitor, and can be considered for future research to develop the new drug against galectin-3.