Molecular Modeling Techniques Research Articles

Modeling Protein Complexes and Molecular Assemblies Using Computational Methods.

Many biological molecules are assembled into supramolecular complexes that are necessary to perform functions in the cell. Better understanding and characterization of these molecular assemblies are thus essential to further elucidate molecular mechanisms and key protein-protein interactions that could be targeted to modulate the protein binding affinity or develop new binders. Experimental access to structural information on these supramolecular assemblies is often hampered by the size of these systems that make their recombinant production and characterization rather difficult. Computational methods combining both structural data, molecular modeling techniques, and sequence coevolution information can thus offer a good alternative to gain access to the structural organization of protein complexes and assemblies. Herein, we present some computational methods to predict structural models of the protein partners, to search for interacting regions using coevolution information, and to build molecular assemblies. The approach is exemplified using a case study to model the succinate-quinone oxidoreductase heterocomplex.

Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Natural Product-based PDE 3/4 Dual Inhibitors for COPD

Background: Chronic Obstructive Pulmonary Disorder (COPD) is a chronic and progressive lung disease with a steady increase in prevalence over the recent years. Current treatment options of COPD are aimed at symptomatic relief without the ability to cure COPD, and certain corticosteroid treatments cause patients to be susceptible to infections. Newer studies have hinted that PDE3/4 dual inhibitors may produce a higher efficacy and better safety profile compared to current alternatives. These novel inhibitors may potentially improve the control of COPD exacerbation without increasing the risk of infections. Thus, our study aimed to identify and refine natural compounds with PDE3/4 dual inhibitory activities through molecular modelling techniques. Method: A two-sided approach through ligand-based and structure-based pharmacophore modelling was employed, followed by virtual screening and molecular docking to identify lead compounds with PDE3/4 dual inhibition activity. Results: Pharmacophore-based screening of Universal Natural Products Database (UNPD) resulted in the identification of one compound for each pharmacophore model, namely UNPD1558 and UNPD139455, with high binding affinities towards both PDE3B and PDE4B. The two compounds were subsequently docked with PDE3B and PDE4B to study their interactions with the active site residues. Structural modifications of the compounds were proposed based on the docking results to optimise their binding affinity and physicochemical properties. Conclusion: Compound 25a4 and compound 28, which were designed based on the structures of UNPD1558 and UNPD139455, respectively, showed an improved binding affinity for both PDE3B and PDE4B. These lead compounds showed promising results as drug candidates, and their PDE3/4 dual inhibitory properties should be further investigated through in vivo and in vivo studies.

Multi‐Spectroscopic and Theoretical Analyses of Human Serum Albumin Binding to a Water‐Soluble Zinc(II) Complex including β‐Amino Alcohol

AbstractIn this study, we examined the interaction process of human serum albumin (HSA) with a water‐soluble zinc(II) complex of dichloro {2‐[N‐(2‐hydroxyethylammonioethyl) imino methyl] phenol} at pH=7.4 and in vitro utilizing molecular docking modeling and spectral techniques. In the multi‐temperature fluorescence test, the consecutive and gradual addition of the zinc(II) complex to the HSA‐containing cell resulted in fluorescence quenching, and it showed that the zinc(II) complex‐protein interaction is associated with a static quenching mechanism; also, the number of binding sites (n) and the binding constant (Kb) were computed by this test. The evaluation of thermodynamic data showed spontaneous progression, and the involvement of hydrogen bonding/van der Waals forces in protein‐zinc(II)complex formation. The site markers competition studies using two drugs, warfarin and ibuprofen, indicated that zinc(II) complex binds to the protein via site I/sub‐domain IIA. The albumin‐zinc(II) complex interaction and the structural alterations in the serum albumin were proved by electronic absorption technique and circular dichroism spectroscopy. Job′s curve exhibited a stoichiometric ratio of 1 : 1 in the HSA‐zinc(II) complex adduct. The accuracy of the results obtained from experimental findings on the interaction between HSA and zinc(II) complex was checked by molecular docking simulation, which illustrated a good agreement between experimental and theoretical data.

Relating Crystal Structure to Surface Properties: A Study on Quercetin Solid Forms.

The surface energy and surface chemistry of a crystal are of great importance when designing particles for a specific application, as these will impact both downstream manufacturing processes as well as final product quality. In this work, the surface properties of two different quercetin solvates (quercetin dihydrate and quercetin DMSO solvate) were studied using molecular (synthonic) modeling and experimental techniques, including inverse gas chromatography (IGC) and contact angle measurements, to establish a relationship between crystal structure and surface properties. The attachment energy model was used to predict morphologies and calculate surface properties through the study of their growth synthons. The modeling results confirmed the surface chemistry anisotropy for the two forms. For quercetin dihydrate, the {010} facets were found to grow mainly by nonpolar offset quercetin–quercetin stacking interactions, thus being hydrophobic, while the {100} facets were expected to be hydrophilic, growing by a polar quercetin–water hydrogen bond. For QDMSO, the dominant facet {002} grows by a strong polar quercetin–quercetin hydrogen bonding interaction, while the second most dominant facet {011} grows by nonpolar π–π stacking interactions. Water contact angle measurements and IGC confirmed a greater overall surface hydrophilicity for QDMSO compared to QDH and demonstrated surface energy heterogeneity for both structures. This work shows how synthonic modeling can help in the prediction of the surface nature of crystalline particles and guide the choice of parameters that will determine the optimal crystal form and final morphology for targeted surface properties, for example, the choice of crystallization conditions, choice of solvent, or presence of additives or impurities, which can direct the crystallization of a specific crystal form or crystal shape.

Comparative binding affinity analysis of dual CDK2/FLT3 inhibitors

AbstractSelective inhibition of cyclin‐dependent kinase 2 (CDK2) using small molecules is gaining popularity for the treatment of certain types of acute myeloid leukemia (AML). In this study, we used different molecular modeling techniques to investigate the structure–activity relationship (SAR) and binding modalities of dual CDK2/FLT3 inhibitors. The key chemical characteristics of the 3H‐pyrazolo[4,3‐f]quinoline derivatives were highlighted as descriptive colored contours using comparative molecular similarity analysis (CoMSIA). Modifying chemical groups in existing compounds along these contours could improve CDK2 selectivity over FMS‐like tyrosine kinase 3 (FLT3). We determined the ligand affinities for CDK2 by estimating the binding free energy using molecular mechanics generalized Born surface area (MM‐GBSA) and umbrella sampling (US) simulations. Reasonable correlations were found between the computed and experimental binding energies, suggesting that MM‐GBSA and US can be used to reliably predict the binding affinities of new compounds in the more potent CDK2 drug development process.

Investigation on conformational variation and enzymatic activity of trypsin affected by Ti3C2 QDs via spectroscopic technique and molecular modeling

In this paper, Ti3C2 quantum dots (Ti3C2 QDs) were synthesized by simply treating Ti3C2 MXene powder with acid and base via hydrothermal method. Ti3C2 QDs exhibited superior fluorescence property and were used for the fluorescent imaging of living HeLa cells successfully. In order to evaluate the influence of Ti3C2 QDs on protease with specific biological functions, binding interaction of Ti3C2 QDs with trypsin was studied comprehensively and deeply through spectroscopic strategies and molecular modeling technique. The intrinsic fluorescence of trypsin was spontaneously quenched by Ti3C2 QDs through static quenching mode under van der Waals interaction force, and Ti3C2 QDs bound with the inactive residue domain of trypsin firmly with stoichiometric ratio of 1:1. Ti3C2 QDs induced the microenvironmental variation of the amino acid residues in trypsin, reducing the thermal stability of trypsin significantly. Gel electrophoresis experiments and microscopic imaging experiments demonstrated that Ti3C2 QDs inhibited the enzymatic activity of trypsin on the digestion of human serum albumin and HeLa cells obviously. These results revealed not only the deep interaction mechanism between Ti3C2 QDs and protease but also the influence of Ti3C2 QDs on the enzymatic activity of trypsin, paving the way for the safe biological application of Ti3C2 QDs in the diagnosis and the therapy of protease-related diseases.

Design of a Structurally Novel Multipotent Drug Candidate by the Scaffold Architecture Technique for ACE-II, NSP15, and Mpro Protein Inhibition: Identification and Isolation of a Natural Product to Prevent the Severity of Future Variants of Covid 19 and a Colorectal Anticancer Drug.

Scaffold architecture in the sectors of biotechnology and drug discovery research include scaffold hopping and molecular modelling techniques and helps in searching for potential drug candidates containing different core structures using computer-based software, which greatly aids medicinal and pharmaceutical chemistry. Going ahead, the computational method of scaffold architecture is thought to produce new scaffolds, and the method is capable of helping search engines toward producing new scaffolds that are likely to represent potent compounds with high therapeutic applications, which is a possibility in this case as well. Here we probate a different interactive design by natural product hopping, molecular modelling, pharmacophore modelling, modification, and combination of the phytoconstituents present in different medicinal plants for developing a pharmacophore-guided good drug candidate for the variants of SARS-CoV-2 or Covid 19. In the modern era, these approaches are carried out at every level of development of scaffold queries, which are increasingly summarized from chemical structures. In this context, we report on a successfully designed drug-like candidate having a high-binding-affinity “compound SLP” by understanding the relationships between the compounds’ pharmacophores, scaffold functional groups, and biological activities beyond their individual applications that abide by Lipinski’s rule of five, Ghose rule, Veber rule etc. The new scaffold generated by altering the core of the known phyto-compounds holds a good predicted ADMET profile and is examined with iMODS server to check the molecular dynamics simulation with normal mode analysis (NMA). The scaffold’s three-dimensional (3D) structure yields a searchable natural product koenimbine from a conformer database having good ADMET property and high availability in spice Murraya koenigii leaves. M. koenigii leaves are easily available in the market, and might ensure the immunity, good health, and well-being of people if affected with any of the variants of Covid 19. The cell viability studies of koenimbine on murine colorectal carcinoma cell line (CT-26) showed no toxicity on normal mice lymphocyte cells (MLCs). The anticancer mechanism of koenimbine was displayed by its enhanced capacity to produce intercellular reactive oxygen species (ROS) in the colorectal carcinoma cell line.

Continuous Manufacturing and Molecular Modeling of Pharmaceutical Amorphous Solid Dispersions.

Amorphous solid dispersions enhance solubility and oral bioavailability of poorly water-soluble drugs. The escalating number of drugs with poor aqueous solubility, poor dissolution, and poor oral bioavailability is an unresolved problem that requires adequate interventions. This review article highlights recent solubility and bioavailability enhancement advances using amorphous solid dispersions (ASDs). The review also highlights the mechanism of enhanced dissolution and the challenges faced by ASD-based products, such as stability and scale-up. The role of process analytical technology (PAT) supporting continuous manufacturing is highlighted. Accurately predicting interactions between the drug and polymeric carrier requires long experimental screening methods, and this is a space where computational tools hold significant potential. Recent advancements in data science, computational tools, and easy access to high-end computation power are set to accelerate ASD-based research. Hence, particular emphasis has been given to molecular modeling techniques that can address some of the unsolved questions related to ASDs. With the advancement in PAT tools and artificial intelligence, there is an increasing interest in the continuous manufacturing of pharmaceuticals. ASDs are a suitable option for continuous manufacturing, as production of a drug product from an ASD by direct compression is a reality, where the addition of multiple excipients is easy to avoid. Significant attention is necessary for ongoing clinical studies based on ASDs, which is paving the way for the approval of many new ASDs and their introduction into the market.

Imidazo[1,2,4]triazolone and fused imidazo[1,2,4]triazolone derivatives: Synthesis, in vitro anticancer screening, CDK2 inhibitory activity, and molecular modeling studies

AbstractIn continuation of our program for synthesizing novel imidazotriazole scaffolds, we report herein the synthesis of new fifteen substituted and fused imidazotriazole derivatives via different addition and cyclocondensation pathways. Thirteen compounds have been tested for their antiproliferative activity against 60 NCI cell lines. Compounds 3, 15 and 17 were the most active among the synthesized series. Imidazo[2,1‐c][1,2,4]triazolone derivative 3 showed high activity against leukemia K‐562 (51.00%), RPMI‐8226 (68.36%) and breast cancer MCF‐7 (56.76%) cell lines. While compound 15 exhibited high potency against colon cancer HCT‐15 (59.33%), CNS cancer SNB‐75 (57.06%) and renal cancer UO‐31 (50.5%) cell lines. Bis[1,2,4]triazolopurin‐7‐one derivative 17 showed strong activity against CNS cancer SNB‐75 cell line (54.32%). Compounds 3, 15 and 17 were evaluated through molecular modeling and docking techniques to give us a closer look on their binding mode with CDK2. The in vitro inhibitory activity against CDK2 was also performed for compounds 3 and 17. Compound 3 was subjected to further investigations by studying its effect on cell cycle progression and cell apoptosis in MCF‐7 cell line. It caused apoptosis, necrosis and induced cell cycle arrest at G2/M phase in MCF‐7 cell.

Insight into the molecular-level details of αs1 casein interactions with IgG: Combining with LC-MS/MS and molecular modelling techniques

αs1-Casein (αs1-CN) is a major cow milk allergen, while the tertiary structure of αs1-CN and conformational epitopes of αs1-CN have not been clarified. Here, a reasonable three-dimensional structure of αs1-CN was established using ab initio methods, and hot-spot residues and epitopes were investigated by combining molecular dynamics simulation, peptides synthesis, and ELISA. Obtained results demonstrated that the binding mechanism between αs1-CN and IgG was located on three main regions: a helical structure zone (E77-Q97), the flexible loop zone (Y154-T174), and a flexible C-terminal (N190-L198), mainly connecting via hydrogen bond and ionic bonds. The hydrolysates produced by papain with lowest antigenicity (12.43%), which could considerably destroy the essential epitopes of αs1-CN confirmed by epitope synthesis, and LC-MS/MS. The results reported herein would provide novel insights into the interface interactions between αs1-CN and IgG, and prove valuable for developing hypoallergenic infant-formula and peptide vaccines for allergen-specific immunotherapy.

Sulfated glycosaminoglycans inhibit transglutaminase 2 by stabilizing its closed conformation

Transglutaminases (TGs) catalyze the covalent crosslinking of proteins via isopeptide bonds. The most prominent isoform, TG2, is associated with physiological processes such as extracellular matrix (ECM) stabilization and plays a crucial role in the pathogenesis of e.g. fibrotic diseases, cancer and celiac disease. Therefore, TG2 represents a pharmacological target of increasing relevance. The glycosaminoglycans (GAG) heparin (HE) and heparan sulfate (HS) constitute high-affinity interaction partners of TG2 in the ECM. Chemically modified GAG are promising molecules for pharmacological applications as their composition and chemical functionalization may be used to tackle the function of ECM molecular systems, which has been recently described for hyaluronan (HA) and chondroitin sulfate (CS). Herein, we investigate the recognition of GAG derivatives by TG2 using an enzyme-crosslinking activity assay in combination with in silico molecular modeling and docking techniques. The study reveals that GAG represent potent inhibitors of TG2 crosslinking activity and offers atom-detailed mechanistic insights.

3D-QSAR, ADME-Tox In Silico Prediction and Molecular Docking Studies for Modeling the Analgesic Activity against Neuropathic Pain of Novel NR2B-Selective NMDA Receptor Antagonists

A new class of selective antagonists of the N-Methyl-D-Aspartate (NMDA) receptor subunit 2B have been developed using molecular modeling techniques. The three-dimensional quantitative structure–activity relationship (3D-QSAR) study, based on comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models, indicate that steric, electrostatic and hydrogen bond acceptor fields have a key function in the analgesic activity against neuropathic pain. The predictive accuracy of the developed CoMFA model (Q2 = 0.540, R2 = 0.980, R2 pred = 0.613) and the best CoMSIA model (Q2 = 0.665, R2 = 0.916, R2 pred = 0.701) has been successfully examined through external and internal validation. Based on ADMET in silico properties, L1, L2 and L3 ligands are non-toxic inhibitors of 1A2, 2C19 and 2C9 cytochromes, predicted to passively cross the blood–brain barrier (BBB) and have the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicate that the active ligands (L1, L2 and L3) interact specifically with Phe176, Glu235, Glu236, Gln110, Asp136 and Glu178 amino acids of the transport protein encoded as 3QEL. Therefore, they could be used as analgesic drugs for the treatment of neuropathic pain.

In silico investigation of Alsin RLD conformational dynamics and phosphoinositides binding mechanism.

Alsin is a protein known for its major role in neuronal homeostasis and whose mutation is associated with early-onset neurodegenerative diseases. It has been shown that its relocalization from the cytoplasm to the cell membrane is crucial to induce early endosomes maturation. In particular, evidences suggest that the N-terminal regulator of chromosome condensation 1 like domain (RLD) is necessary for membrane association thanks to its affinity to phosphoinositides, membrane lipids involved in the regulation of several signaling processes. Interestingly, this domain showed affinity towards phosphatidylinositol 3-phosphate [PI(3)P], which is highly expressed in endosomes membrane. However, Alsin structure has not been experimentally resolved yet and molecular mechanisms associated with its biological functions are mostly unknown. In this work, Alsin RLD has been investigated through computational molecular modeling techniques to analyze its conformational dynamics and obtain a representative 3D model of this domain. Moreover, a putative phosphoinositide binding site has been proposed and PI(3)P interaction mechanism studied. Results highlight the substantial conformational stability of Alsin RLD secondary structure and suggest the role of one highly flexible region in the phosphoinositides selectivity of this domain.

Structural aspects of formetanate hydrochloride binding with human serum albumin using spectroscopic and molecular modeling techniques

Formetanate Hydrochloride (FMT), a highly potent chemical, acts as an insecticide, acaricide, and miticide to protect various fruits and vegetables. The widespread use elevates concern about its presence in the ecosystem, impact upon human health via interaction with biological receptors. Spectroscopic and molecular modeling techniques at different temperatures were used to investigate the binding of FMT with Human serum albumin (HSA) at the molecular level. The experimental and computational results have provided the binding affinity, binding mode, conformational flexibility, and thermodynamic profile of FMT-HSA complex. The FMT binding appears to be spontaneous, and entropy driven. Overall binding affinity of FMT falls within −7.29 to −4.67 Kcal M-1. FMT binds in domain I, subdomain IA of HSA and is stabilized by hydrophobic interactions. Molecular dynamics simulations of the FMT-HSA complex over 100 ns at 288 K, 298 K and 308 K indicated that FMT showed minor adjustments in conformation and placement within the binding site. While, MM/PBSA analysis of the complex provided individual contributions of energy terms. Quantum mechanical (QM) calculations were used to calculate absolute energy values of different poses of FMT which in turn showed minor variations in energy suggesting slight conformational variation in the bound form. The computational results are in agreement with experimental findings.

Binding Studies and Lead Generation of Pteridin-7(8H)-one Derivatives Targeting FLT3.

Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8H)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3D835Y) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein–ligand binding affinity by employing molecular mechanics Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure–activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC50 values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.

Targeting Streptomyces-Derived Streptenol Derivatives against Gynecological Cancer Target PIK3CA: An In Silico Approach.

Streptomyces is amongst the most amenable genera for biotechnological applications, and it is extensively used as a scaffold for drug development. One of the most effective therapeutic applications in the treatment of cancer is targeted therapy. Small molecule therapy is one of them, and it has gotten a lot of attention recently. Streptomyces derived compounds namely streptenols A, C, and F–I and streptazolin were subjected for ADMET property assessment. Our computational studies based on molecular docking effectively displayed the synergistic effect of streptomyces-derived compounds on the gynecological cancer target PIK3CA. These compounds were observed with the highest docking scores as well as promising intermolecular interaction stability throughout the molecular dynamic simulation. Molecular docking and molecular dynamic modeling techniques were utilized to investigate the binding mode stability of drugs using a pharmacophore scaffold, as well as physicochemical and pharmacokinetic aspects linked to alpelisib. With a root mean square fluctuation of the protein backbone of less than 0.7 nm, they demonstrated a steady binding mode in the target binding pocket. They have also prompted hydrogen bonding throughout the simulations, implying that the chemicals have firmly occupied the active site. A comprehensive study showed that streptenol D, streptenol E, streptenol C, streptenol G, streptenol F, and streptenol B can be considered as lead compounds for PIK3CA-based inhibitor design. To warrant the treatment efficacy against cancer, comprehensive computational research based on proposed chemicals must be assessed through in vitro studies.

Descifrando el mecanismo de inhibición de una pseudoquinasa: la quinasa ligada a integrinas y el cpd22

According to World Health Organization (WHO) cancer is one of top non- infectious death causes worldwide. In this context, as such the searching of new potent and safe anticancer drugs is a hot point for pharmacy industry and academic investigation. Despite protein kinases have been one of the most explored anticancer targets, its evolutionary degenerated parents, pseudokinases, have attracted the attention of scientific community during the last decade. Integrin Linked Kinase (ILK) is a member of the human pseudokinome that has been claimed and validated as a prommissing target for neoplastic diseases. The only well-known ILK inhibitor, CPD22, has probed its activity in phenotypic assays, however very few knowledge regarding its mechanism of action at molecular level is available. Using chemoinformatic and molecular modelling techniques we were able to elucidate if this molecule is able to bind to ILK and how. Additionally, our model explains the SAR raised from the optimization campaign, and SPR experiments have probed, by first time, that this molecule binds to ILK, thus supporting the hypothesis of inhibition by direct binding and the computational model as well.

Molecular Docking and In Silico Simulation of Trichinella spiralis Membrane-Associated Progesterone Receptor Component 2 (Ts-MAPRC2) and Its Interaction with Human PGRMC1.

Background. Trichinellosis is a foodborne zoonotic disease caused by Trichinella spp., including Trichinella spiralis. This parasitic disease ranks as seven of the most infectious in the world. In this context, it is important to develop a vaccine that can combat Trichinellosis, especially for humans and pigs. This would be an important step in preventing transmission. In this study, we focus on homology modelling, binding site prediction, molecular modelling, and simulation techniques used to explore the association between Trichinella spiralis membrane-associated progesterone receptor component 2 (Ts-MAPRC2) and the human PGRMC1 protein. It was found that the progesterone receptor component 2 of T. spiralis has 44.54% sequence identity with human PGRMC1 (PDB ID: 4X8Y). Binding sites predicted for human PGRMC1 are GLU 7, PHE 8, PHE 10, PHE 18, LEU 27, ASP 36, and VAL 104. Molecular docking has six clusters based on Z scores. They range from -1.5 to 1.8. It was found that the progesterone receptor component 2 of T. spiralis has 44.54% sequence identity with human PGRMC1. During simulation, the average RMSD was 2.44 ± 0.20 Å, which indicated the overall stability of the protein. Based on docking studies and computational simulations, we hypothesized that the interaction of the proteins Trichinella spiralis membrane-associated progesterone receptor component 2 and human PGRMC1 formed stable complexes. The discovery of Ts-MAPRC2 may pave the way for the development of drugs and vaccines to treat Trichinellosis.

Exploring the intercalation binding of tiamulin with DNA using multispectroscopy and a molecular modelling approach.

The binding of tiamulin with calf thymus DNA was systematically investigated using multispectroscopy and molecular modelling techniques. For DNA, once tiamulin was added, viscosity (η) and melting temperature (Tm ) both exhibited an uptrend. The fluorescence performance of the tiamulin-DNA complex did not change with the ionic strength changes. The binding constant (Ka ) of tiamulin for single-stranded DNA (ssDNA, 1.48 × 104 M-1 ) was obviously higher than that for double-stranded DNA (dsDNA, 9.51 × 103 M-1 ) at 291 K. The helix structure became looser and the base stack force became stronger for DNA due to the presence of tiamulin as seen from circular dichroic (CD) spectra. The intercalation binding mode of tiamulin with DNA was disclosed. Molecular modelling also revealed tiamulin inserting into the base pairs with the lowest binding free energy of -18.73 kJ mol-1 using van der Waals forces as well as hydrogen bonds.

Molecular dynamics simulations of exchange behavior of radionuclides into montmorillonite: Unraveling the dynamic processes and microscopic structures

The reliability of long-term safety assessments of radioactive waste repositories can be improved by a molecular-level knowledge of the geochemical processes onto clay minerals, such as montmorillonite. However, a mechanistic understanding of the dynamic exchange processes of radionuclides into the interlayer region of montmorillonite is still unclear. Using molecular modeling technique, we elucidate the dynamic exchange characteristics, microscopic structures, aqueous species distributions, and diffusion properties of the exchange of radioactive nuclides. The exchange ratios are in the order of Cs+ ≈ Rb+ ≈ UO22+ > > Ba2+ ≈ Sr2+ > > Eu3+, and Cl− can enter the interlayer space by associating with nuclides. Formation of aqueous CO32−-UO22+ clusters largely reduces exchange amount. Unlike CO32−, other anions (Cl−, I−, SO42−, and TcO4−) show relatively weaker binding ability with UO22+. We find that multivalent cations prefer to stay in the mid-plane of interlayer region and Cs+ and Rb+ are located closer to the basal plane via inner-sphere complexation. Furthermore, the orientations of interlayer UO22+ are nearly perpendicular to basal surface. The effects of temperature, montmorillonite type, interlayer water content, and concentration of nuclide on the exchange processes are further clarified. This study provides fundamental data for a profound understanding of environmental behavior of radionuclides.