Combined Molecular Dynamics Research Articles

Stabilization of delphinidin-3-O-rutinoside by mixed β-conglycinin and hydrolysates of glycinin upon heating

The selectively hydrolyzed soy protein composed of β-conglycinin (7S) and glycinin hydrolysates (GH) showed a superior protective effect on the delphinidin-3-O-rutinoside (D3R) during the steaming of colored wheat dough. To clarify the potential mechanism, 7S and GH were isolated and combined in varied ratios to mimic the RG proteins, and the interactions between proteins and D3R were studied by combined multispectral and molecular dynamics simulation study. The results suggested that 7S showed a higher stabilization effect of D3R than GH upon heating. In contrast, the optimum effect was noticed when incorporated with the mixed proteins with equal level of 7S and GH. D3R induced conformational changes of 7S and GH upon heating, and D3R formed complexes with proteins via hydrophobic interactions, and it was a static quenching process. The optimal binding affinity to D3R was observed with equal level of GH and 7S, contributing to enhanced thermal stability. Compared with GH, 7S could bind more amino acids and form a more stable complex with D3R. The results of this study could provide a theoretical basis for the preservation of D3R upon thermal processing and promote the application of mixed soy proteins in the functional food industry.

Unravelling the interactions between small molecules and liposomal bilayers via molecular dynamics and thermodynamic modelling

Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients – ranging from small molecule drugs to proteins and nucleic acids – these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility.This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.

Hydrostatic pressure effect on excited state properties of room temperature phosphorescence molecules: A QM/MM study

Stimulus-responsive organic room temperature phosphorescence (RTP) materials exhibit variations in their luminescent characteristics (lifetime and efficiency) upon exposure to external stimuli, including force, heat, light and acid-base conditions, the development of stimulus-responsive RTP molecules becomes imperative. However, the inner responsive mechanism is unclear, theoretical investigations to reveal the relationship among hydrostatic pressures, molecular structures and photophysical properties are highly desired. Herein, taking the Se-containing RTP molecule (SeAN) as a model, based on the dispersion corrected density functional theory (DFT-D), the combined quantum mechanics and molecular dynamics (QM/MM) method and thermal vibration correlation function (TVCF) theory, the influences of hydrostatic pressure on molecular structures, transition properties as well as lifetimes and efficiencies of RTP molecule are theoretically studied. Results show that extended lifetime and enhanced efficiency are observed at 2 Gpa compared with molecule at normal pressure, and this is related with the small reorganization energy and large oscillator strength. Moreover, due to the small energy gap (0.34 eV) and remarkable spin-orbit coupling (SOC) constant (8.56 cm-1) between first singlet excited state and triplet state, fast intersystem crossing (ISC) process is determined for molecule at 6 Gpa. Furthermore, the intermolecular interactions are visualized using independent gradient model based on Hirshfeld partition (IGMH) and the changes of molecular packing modes, SOC values, lifetimes and efficiencies with pressures are detected. These results reveal the relationship between molecular structures and RTP properties. Our work provides theoretical insights into the hydrostatic pressure response mechanism and could promote the development new efficient stimulus-responsive molecules.

Water Solvent Reorganization upon Ultrafast Resonant Stimulated X-ray Raman Excitation of a Metalloporphyrin Dimer.

We propose an X-ray Raman pump-X-ray diffraction probe scheme to follow solvation dynamics upon charge migration in a solute molecule. The X-ray Raman pump selectively prepares a valence electronic wavepacket in the solute, while the probe provides information about the entire molecular ensemble. A combination of molecular dynamics and ab initio quantum chemistry simulations is applied to a Zn-Ni porphyrin dimer in water. Using time-resolved X-ray diffraction and pair distribution functions, we extracted solvation shell dynamics.

Electronic Properties of DNA Origami Nanostructures Revealed by In Silico Calculations.

DNA origami is a pioneering approach for producing complex 2- or 3-D shapes for use in molecular electronics due to its inherent self-assembly and programmability properties. The electronic properties of DNA origami structures are not yet fully understood, limiting the potential applications. Here, we conduct a theoretical study with a combination of molecular dynamics, first-principles, and charge transmission calculations. We use four separate single strand DNAs, each having 8 bases (4 × G4C4 and 4 × A4T4), to form two different DNA nanostructures, each having two helices bundled together with one crossover. We also generated double-stranded DNAs to compare electronic properties to decipher the effects of crossovers and bundle formations. We demonstrate that density of states and band gap of DNA origami depend on its sequence and structure. The crossover regions could reduce the conductance due to a lack of available states near the HOMO level. Furthermore, we reveal that, despite having the same sequence, the two helices in the DNA origami structure could exhibit different electronic properties, and electrode position can affect the resulting conductance values. Our study provides better understanding of the electronic properties of DNA origamis and enables us to tune these properties for electronic applications such as nanowires, switches, and logic gates.

Computational insights into allosteric inhibition of focal adhesion kinase: A combined pharmacophore modeling and molecular dynamics approach

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that modulates integrin and growth factor signaling pathways and is implicated in cancer cell migration, proliferation, and survival. Over the past decade various, FAK kinase, FERM, and FAT domain inhibitors have been reported and a few kinase domain inhibitors are under clinical consideration. However, few of them were identified as multikinase inhibitors. In kinase drug design selectivity is always a point of concern, to improve selectivity allosteric inhibitor development is the best choice. The current research utilized a pharmacophore modeling (PM) approach to identify novel allosteric inhibitors of FAK. The all-available allosteric inhibitor bound 3D structures with PDB ids 4EBV, 4EBW, and 4I4F were utilized for the pharmacophore modeling. The validated PM models were utilized to map a database of 770,550 compounds prepared from ZINC, EXIMED, SPECS, ASINEX, and InterBioScreen, aiming to identify potential allosteric inhibitors. The obtained compounds from screening step were forwarded to molecular docking (MD) for the prediction of binding orientation inside the allosteric site and the results were evaluated with the known FAK allosteric inhibitor (REF). Finally, 14 FAK-inhibitor complexes were selected from the docking study and were studied under molecular dynamics simulations (MDS) for 500 ns. The complexes were ranked according to binding free energy (BFE) and those demonstrated higher affinity for allosteric site of FAK than REF inhibitors were selected. The selected complexes were further analyzed for intermolecular interactions and finally, three potential allosteric inhibitor candidates for the inhibition of FAK protein were identified. We believe that identified scaffolds may help in drug development against FAK as an anticancer agent.

A Theoretical Study of Oxygen Anion Diffusion through the A-Site Deficient SrTiO3 Lattice Structure: A Machine Learning Approach.

The performance of strontium titanate-based perovskite materials, widely employed as electrode materials for reversible solid oxide cells, is directly characterized by their efficiency and their ability to facilitate the diffusion of generated oxygen ions. A technique frequently employed for enhancing oxygen ion diffusivity involves artificially generating A-site vacancies in these structures. In this study, the molecular-level mechanism of oxygen ion diffusion for a range of A-site deficient structures is extensively investigated using combined molecular dynamics simulations and machine learning-based technique. The analysis of molecular simulation trajectories yields diffusion parameters for the bulk system. Additionally, clustering analysis of time-overlapped locations of oxygen ions provides a spatial distribution of oxygen ion dislocations. Concurrently, tracking the motion of individual oxygen ions elucidates the contribution of each ion to the overall ionic conductance. Overall, the systematic generation of A-site deficiency is found to significantly influence oxygen ion dislocations, thereby impacting the performance of these materials in terms of oxide ion conduction.

Effects of leucine on hydrate formation: A combined experimental and molecular dynamics study

Compared to conventional natural gas storage and transportation methods, hydrates offer a safer, more compact alternative with broad future potential. To enhance hydrate formation, there has been considerable interest in environmentally friendly and cost-effective amino acid promoters, such as leucine. This study utilized a transparent vessel for CH4 hydrate formation experiments, identifying the optimal 0.5–0.6 wt% leucine concentration, which led to enhanced gas consumption, shorter induction time, and maximum gas storage density. In the leucine system, hydrates exhibited distinctive branching growth on container walls, both upward and downward. The formation of numerous microchannels amplified capillary effects, enhancing gas–liquid contact and fostering hydrate formation. Simultaneously, isobaric-isothermal molecular dynamics (MD) simulations integrated system growth configurations, structural parameters, radial distribution functions, energy barriers and mean square displacements, unveiling leucine’s microscopic impact on hydrate formation. Simulation results unequivocally show that leucine significantly accelerates CH4 hydrate growth by momentarily adsorbing at the solid–liquid interface, expediting water molecule ordering into cage-like structures. Leucine also enhances water molecule structural order around the mobile leucine molecule. Moreover, leucine lowers the energy barrier for methane transitioning from gas to liquid, facilitating gas molecule diffusion into the liquid phase and affording plenty interaction time for water and methane molecules, thereby providing favorable conditions for hydrate formation. These findings provide crucial perspectives for future research in the field of eco-friendly hydrate promoters, paving the way for innovative solutions in natural gas storage and transportation.

Predictive insights into plant-based compounds as fibroblast growth factor receptor 1 inhibitors: a combined molecular docking and dynamics simulation study

The discovery of novel therapeutic agents with potent anticancer activity remains a critical challenge in drug development. Natural products, particularly bioactive phytoconstituents derived from plants, have emerged as promising sources for anticancer drug discovery. In this study, we used virtual screening techniques to explore the potential of bioactive phytoconstituents as inhibitors of fibroblast growth factor receptor 1 (FGFR1), a key signaling protein implicated in cancer progression. We used virtual screening techniques to analyze phytoconstituents extracted from the IMPPAT 2.0 database. Our primary objective was to discover promising inhibitors of FGFR1. To ensure the selection of promising candidates, we initially filtered the molecules based on their physicochemical properties. Subsequently, we performed binding affinity calculations, PAINS, ADMET, and PASS filters to identify nontoxic and highly effective hits. Through this screening process, one phytocompound, namely Mundulone, emerged as a potential lead. This compound demonstrated an appreciable affinity for FGFR1 and exhibited specific interactions with the ATP-binding site residues. To gain further insights into the conformational dynamics of Mundulone and the reference FGFR1 inhibitor, Lenvatinib, we conducted time-evolution analyses employing 200 ns molecular dynamics simulations (MDS) and essential dynamics. These analyses provided valuable information regarding the dynamic behavior and stability of the compounds in complexes with FGFR1. Overall, the findings indicate that Mundulone exhibits promising binding affinity, specific interactions, and favorable drug profiles, making it a promising lead candidate. Further experimental analysis will be necessary to confirm its effectiveness and safety profiles for therapeutic advancement in the cancer field. Communicated by Ramaswamy H. Sarma

A damage-tolerant hybrid aluminum composite reinforced with carbon nanotube and zirconia: study of strengthening mechanisms by combined experiments and molecular dynamics simulations

Aluminum composites, reinforced with CNT and ZrO2 particles, were synthesized via powder metallurgy, undergoing mechanical testing and molecular dynamics (MD) simulations. Hybrid reinforcement significantly increased strength and hardness while preserving toughness through extrinsic toughening mechanisms, preventing a substantial drop in energy absorption. MD simulations revealed dislocation nucleation at reinforcement interfaces, enhancing material strength during propagation. Various reinforcements activated specific strengthening mechanisms, quantified by models. The hybrid composite exhibited excellent strength enhancement and maintained toughness up to a specific reinforcement content. Despite a reduction in energy absorption, the remarkable strength improvement suggests synergistic reinforcement effects, suitable for high-performance, lightweight materials.

Design of New Schiff Bases and Their Heavy Metal Ion Complexes for Environmental Applications: A Molecular Dynamics and Density Function Theory Study.

Schiff bases (SBs) are important ligands in coordination chemistry due to their unique structural properties. Their ability to form complexes with metal ions has been exploited for the environmental detection of emerging water contaminants. In this work, we evaluated the complexation ability of three newly proposed SBs, 1-3, by complete conformational analysis, using a combination of Molecular Dynamics and Density Functional Theory studies, to understand their ability to coordinate toxic heavy metal (HMs) ions. From this study, it emerges that all the ligands present geometries that make them suitable to complex HMs through the N-imino moieties or, in the case of 3, with the support of the oxygen atoms of the ethylene diether chain. In particular, this ligand shows the most promising coordination behavior, particularly with Pb2+.

Computational study and ion diffusion analyses of native defects and indium alloying in β-Ga2O3 structures

Wide band gap semiconductors like gallium oxide are promising materials for high-power optoelectronic device applications. We show here a combined density functional theory and molecular dynamics study of diffusion pathways for different defects in β-Ga2O3. Molecular dynamics simulations result in a smaller equilibrium volume compared to density functional theory, but the overall lattice remains relatively unchanged even with the inclusion of defects, outside of the local distortions that occur to accommodate the presence of a defect. Slight thermal expansion occurs with elevated temperature and a combination of electron localization function and Bader charge analysis reveals that the oxygen interstitial is the most mobile defect as temperature is increased. However, interstitial cations may diffuse at elevated temperature due to a relatively small amount of charge transfer between the defect and lattice. The mobile oxygen defects are shown to increase the mobility of oxygen ions from the lattice, which can be beneficial for electrochemical applications when controlled through annealing processes.

Dynamical Effects of Solvation on Norbornadiene/Quadricyclane Systems.

Molecules that can undergo reversible chemical transformations following the absorption of light, the so-called molecular photoswitches, have attracted increasing attention in technologies, such as solar energy storage. Here, the optical and thermochemical properties of the photoswitch are central to its applicability, and these properties are influenced significantly by solvation. We investigate the effects of solvation on two norbornadiene/quadricyclane photoswitches. Emphasis is put on the energy difference between the two isomers and the optical absorption as these are central to the application of the systems in solar energy storage. Using a combined classical molecular dynamics and quantum mechanical/molecular mechanical computational scheme, we showcase that the dynamic effects of solvation are important. In particular, it is found that standard implicit solvation models generally underestimate the energy difference between the two isomers and overestimate the strength of the absorption, while the explicit solvation spectra are also less red-shifted than those obtained using implicit solvation models. We also find that the absorption spectra of the two systems are strongly correlated with specific dihedral angles. Altogether, this highlights the importance of including the dynamic effects of solvation.

Cleaving DNA with DNA: Cooperative Tuning of Structure and Reactivity Driven by Copper Ions.

A copper-dependent self-cleaving DNA (DNAzyme or deoyxyribozyme) previously isolated by in vitro selection has been analyzed by a combination of Molecular Dynamics (MD) simulations and advanced Electron Paramagnetic Resonance (Electron Spin Resonance) EPR/ESR spectroscopy, providing insights on the structural and mechanistic features of the cleavage reaction. The modeled 46-nucleotide deoxyribozyme in MD simulations forms duplex and triplex sub-structures that flank a highly conserved catalytic core. The DNA self-cleaving construct can also form a bimolecular complex that has a distinct substrate and enzyme domains. The highly dynamic structure combined with an oxidative site-specific cleavage of the substrate are two key-aspects to elucidate. By combining EPR/ESR spectroscopy with selectively isotopically labeled nucleotides it has been possible to overcome the major drawback related to the "metal-soup" scenario, also known as "super-stoichiometric" ratios of cofactors versus substrate, conventionally required for the DNA cleavage reaction within those nucleic acids-based enzymes. The focus on the endogenous paramagnetic center (Cu2+ ) here described paves the way for analysis on mixtures where several different cofactors are involved. Furthermore, the insertion of cleavage reaction within more complex architectures is now a realistic perspective towards the applicability of EPR/ESR spectroscopic studies.

In silico drug derivatives for KRAS-G12D: free-energy surfaces in aqueous solution by well-tempered metadynamics simulations

KRAS oncogenes are the largest family of mutated RAS isoforms, participating in about 30% of all cancers. Due to their paramount medical importance, enormous effort is being devoted to the development of inhibitors using clinical tests, wet-lab experiments and drug design, being this a preliminary step in the process of creating new drugs, prior to synthesis and clinical testing. One central aspect in the development of new drugs is the characterisation of all species that can be used for treatment. In this aim, we propose a computational framework based on combined all-atom molecular dynamics and metadynamics simulations in order to accurately access the most stable conformational variants for several derivatives of a recently proposed small-molecule, called DBD15-21-22. Free energy calculations are essential to unveil mechanisms at the atomic scale like binding affinities or dynamics of stable states. Considering specific atom-atom distances and torsional angles as reliable reaction coordinates we have obtained free-energy landscapes by well-tempered metadynamics simulations, revealing local and global minima of the free-energy hypersurface. We have observed that a variety of stable states together with transition states are clearly detected depending on the particular species, leading to predictions on the behaviour of such compounds in ionic aqueous solution.

Mechanisms of plastic deformation and mechanical strengthening in nano-scale Ti-Ti2Cu eutectoids: A study combined molecular dynamics simulation and experiment

Ti-Cu eutectoid or near-eutectoid alloys were found to possess exceptional high strength owning to the nano-scale lamellar structure of Ti2Cu and α-Ti after additive manufacturing, they are potential candidates for high-performance materials. To reveal the deformation and strengthening mechanisms, the molecular dynamics (MD) simulations and experimental analysis were carried out upon Ti-Ti2Cu lamellae. In this work, we focused on revealing the interface dislocations (IDs) pattern and its effects on the dynamic evolution of the lattice dislocations (LDs) at the Ti/Ti2Cu interface with (0001)α//(01‾3)Ti2Cu orientation relationship. Atomistic simulations depicted that the equilibrium Ti/Ti2Cu interface contains three groups of partial dislocations which dictate two interfacial coherent structures with low stacking fault energy. Each ID consists of several segments, connected by atomic steps with identical direction. The nucleation sites of LDs under external loading locate at the intersection between the dislocation segment and the atomic step, which is related to the local high atom strain. Under compression deformation, the 〈100〉{011} and 〈331〉{103} slip systems in Ti2Cu, and the 〈112¯3〉{101¯1} slip system in α-Ti are activated, achieving a co-deformation mechanism in the Ti-Ti2Cu multilayers. The dislocation-interface interactions are responsible for the deformation plasticity and in turn governs the mechanical strengthening. During nanoindentation tests, larger hardness (∼6.2 GPa) and smaller activation volume (∼12b3) were found in the Ti-Ti2Cu lamellae, which is mainly ascribed to the presence of high-density lamellae interface and confined layer slip, resulting in interface-mediated dislocation annihilation/deposition and consequent high strain hardening. The MD simulations, nanoindentation tests and TEM investigations of interlayer dislocation activity support the strengthening mechanism of dislocation-interface interactions.

Boundary slip and lubrication mechanisms of organic friction modifiers with effect of surface moisture

Surface moisture or humidity impacting the lubrication property is a ubiquitous phenomenon in tribological systems, which is demonstrated by a combination of molecular dynamics (MD) simulation and experiment for the organic friction modifier (OFM)-containing lubricant. The stearic acid and poly-α-olefin 4cSt (PAO4) were chosen as the OFM and base oil molecules, respectively. The physical adsorption indicates that on the moist surface water molecules are preferentially adsorbed on friction surface, and even make OFM adsorption film thoroughly leave surface and mix with base oil. In shear process, the adsorption of water film and desorption OFM film are further enhanced, particularly under higher shear rate. The simulated friction coefficient (that is proportional to shear rate) increases firstly and then decreases with thickening water film, in good agreement with experiments, while the slip length shows a contrary change. The wear increases with humidity due to tribochemistry revealing the continuous formation and removal of Si-O-Si network. The tribological discrepancy of OFM-containing lubricant in dry and humid conditions is attributed to the slip plane’s transformation from the interface between OFM adsorption film and lubricant bulk to the interface between adsorbed water films. This work provides a new thought to understand the boundary lubrication and failure of lubricant in humid environments, likely water is not always harmful in oil lubrication systems.

Interfacial structures and dissociation reactions of protic ionic liquids on Li metal surface: A combined first-principles and ab initio molecular dynamics investigation

Interfacial structures and dissociation reactions of protic ionic liquids (PILs) comprising five protic cations with two common sulfonylimide anions on the Li(001) surface were investigated using first-principles calculations and ab initio molecular dynamics simulations. Both the anions rapidly decompose, yielding LiF, Li2O and Li2S species as well as large fragments, e.g. NSO2CF3 and NSO2. Particularly, the proton attached to the N atom generally segregates from the cations and generates LiOH with the O atom from the anions and the surface Li atom. In addition, detailed comparisons of reaction mechanisms between PIL-based and AIL-based systems were also made.

Adsorption mechanism of alkylphenol ethoxylates surfactants (APEO) on anthracite surface: A combined experimental, DFT and molecular dynamics study

The serious hazards posed by inhalable coal dust to the safety, air purity, and health of coal miners can be effectively alleviated through the use of appropriate dust suppressants. The wetting enhancement capabilities of two dust suppressants, octylphenol polyoxyethylene ether (OP-10) and nonylphenol polyoxyethylene ether (NP-10), were examined in this study through experimental and simulation methods. Macroscopic experiments (surface tension, contact angle, coal dust settling time, and water retention) indicate that the shorter the alkyl chain attached to the benzene ring in the surfactant and the lower the surface tension, the more conducive it is to improving the fluidity and suspension stability of anthracite particles in the wetting solution and further improving the interfacial properties and wetting effect between coal dust and the liquid medium. Mesoscopic experiments (laser particle size, FTIR, XPS, UV–visible spectroscopy, BET, and SEM) showed that the relevant properties of APEO-modified coals were greatly changed, especially the anthracite modified with short-chain alkyl groups of OP-10, which exhibited a stronger aggregation effect on the coal dust particles and increased the pore structure and specific surface area of the coal dust. Additionally, the hydrophilic functional groups are augmented, leading to a notable enhancement in the adsorption capacity of OP-10 on the coal surface. Microscopic simulations (Density Functional Theory calculations, Molecular Dynamics simulations) reveal that APEO surfactants with longer alkyl side chains attached to benzene rings hinder the π-π interactions between the coal's aromatic ring structures and the benzene rings in the surfactants. The surface polarity of coal modified with OP-10 is significantly enhanced, resulting in a more pronounced improvement in wetting performance and an increased water retention capability. The study systematically explores surfactant microstructure effects on anthracite wetting, laying essential groundwork for advanced dust suppression system development.

Counterion Effect in Cobaltate‐Catalyzed Alkene Hydrogenation

AbstractWe show that countercations exert a remarkable influence on the ability of anionic cobaltate salts to catalyze challenging alkene hydrogenations. An evaluation of the catalytic properties of [Cat][Co(η4‐cod)2] (Cat=K (1), Na (2), Li (3), (Depnacnac)Mg (4), and N(nBu)4 (5); cod=1,5‐cyclooctadiene, Depnacnac={2,6‐Et2C6H3NC(CH3)}2CH)]) demonstrated that the lithium salt 3 and magnesium salt 4 drastically outperform the other catalysts. Complex 4 was the most active catalyst, which readily promotes the hydrogenation of highly congested alkenes under mild conditions. A plausible catalytic mechanism is proposed based on density functional theory (DFT) investigations. Furthermore, combined molecular dynamics (MD) simulation and DFT studies were used to examine the turnover‐limiting migratory insertion step. The results of these studies suggest an active co‐catalytic role of the counterion in the hydrogenation reaction through the coordination to cobalt hydride intermediates.