A non-B DNA binding peptidomimetic channel alters cellular functions.

DNA binding transcription factors possess the ability to interact with lipid membranes to construct ion-permeable pathways. Herein, we present a thiazole-based DNA binding peptide mimic TBP2, which forms transmembrane ion channels, impacting cellular ion concentration and consequently stabilizing G-quadruplex DNA structures. TBP2 self-assembles into nanostructures, e.g., vesicles and nanofibers and facilitates the transportation of Na+ and K+ across lipid membranes with high conductance (~0.6 nS). Moreover, TBP2 exhibits increased fluorescence when incorporated into the membrane or in cellular nuclei. Monomeric TBP2 can enter the lipid membrane and localize to the nuclei of cancer cells. The coordinated process of time-dependent membrane or nuclear localization of TBP2, combined with elevated intracellular cation levels and direct G-quadruplex (G4) interaction, synergistically promotes formation and stability of G4 structures, triggering cancer cell death. This study introduces a platform to mimic and control intricate biological functions, leading to the discovery of innovative therapeutic approaches.

Screening 2D Materials for Their Nanotoxicity toward Nucleic Acids and Proteins: An In Silico Outlook.

Since the discovery of graphene, two-dimensional (2D) materials have been anticipated to demonstrate enormous potential in bionanomedicine. Unfortunately, the majority of 2D materials induce nanotoxicity via disruption of the structure of biomolecules. Consequently, there has been an urge to synthesize and identify biocompatible 2D materials. Before the cytotoxicity of 2D nanomaterials is experimentally tested, computational studies can rapidly screen them. Additionally, computational analyses can provide invaluable insights into molecular-level interactions. Recently, various "in silico" techniques have identified these interactions and helped to develop a comprehensive understanding of nanotoxicity of 2D materials. In this article, we discuss the key recent advances in the application of computational methods for the screening of 2D materials for their nanotoxicity toward two important categories of abundant biomolecules, namely, nucleic acids and proteins. We believe the present article would help to develop newer computational protocols for the identification of novel biocompatible materials, thereby paving the way for next-generation biomedical and therapeutic applications based on 2D materials.

Computational Assessment of the Biocompatibility of Two-Dimensional g-C3N3 Toward Lipid Membranes.

One of the most recent additions to the family of two-dimensional (2D) materials, graphitic C3N3 (g-C3N3), has been considered a viable contender for biomedical applications, although its potential toxicity remains elusive. We perform all-atom molecular dynamics simulations to decipher the interactions between model lipid membranes and g-C3N3 as a first step toward exploring the cytotoxicity induced at the nanoscale. We show that g-C3N3 can easily insert into the cellular membranes following a multistage mechanism consisting of simultaneous desolvation of the 2D material along with enrichment of nanomaterial-lipid interactions. Free energy calculations indicate that g-C3N3 is more stable in a membrane-bound state compared to an aqueous solution; however, the insertion of the material does not disturb the structural integrity of lipid membranes. After being inserted into a membrane, g-C3N3 is unlikely to be released into the cellular environment and is incapable of extracting lipid molecules from the membrane. The nature of interaction between the 2D material and membranes is found to be independent of the nanomaterial size. Also, the performance of g-C3N3 toward biomolecular delivery is shown to be significantly improved compared to the state-of-the-art 2D materials graphene and hexagonal boron nitride (h-BN). It is revealed that, the affinity of g-C3N3 toward lipid membranes is weaker compared to the nanotoxic graphene and h-BN, while being marginally higher than h2D-C2N, which in turn, increases the biocompatibility of the material, thereby brightening its future as a noncytotoxic material for forthcoming biomedical applications.

Two dimensional materials are non-nanotoxic and biocompatible towards cyclotides: evidence from classical molecular dynamics simulations.

Cyclotides are backbone-cyclized peptides of plant origin enriched with disulfide bonds, having exceptional stability towards thermal denaturation and proteolytic degradation. They have a plethora of activities like antibacterial, antifungal, anti-tumor and anti-HIV properties predominantly owing to their selective interaction with certain phospholipids, thereby leading to the disruption of cellular membranes. On the other hand, low-dimensional materials like graphene and hexagonal boron nitride (h-BN) are also known to show membrane-proliferating activities through lipid extraction. A plausible and more effective antibacterial, anti-tumor and antifungal agent would be a composite of these 2D materials and cyclotides, provided the structures of the peptides remain unperturbed upon adsorption and interaction. In this study, classical molecular dynamics simulations are performed to understand the nature of adsorption of cyclotides belonging to different families on graphene and h-BN and analyze the resulting structural changes. It is revealed that, due to their exceptional structural stability, cyclotides maintain their structural integrity upon adsorption on the 2D materials. In addition, the aggregated states of the cyclotides, which are ubiquitous in plant organs, are also not disrupted upon adsorption. Extensive free energy calculations show that the adsorption strength of the cyclotides is moderate in comparison to those of other similar-sized biomolecules, and the larger the size of the aggregates, the weaker the binding of individual peptides with the 2D materials, thereby leading to their lower release times from the materials. It is predicted that graphene and h-BN may safely be used for the preparation of composites with cyclotides, which in turn may be envisaged to be probable candidates for manufacturing next-generation bionano agents for agricultural, antibacterial and therapeutic applications.

Thiazole Containing PNA Mimic Regulates c-MYC Gene Expression through DNA G-Quadruplex.

Peptide nucleic acids (PNAs), besides hybridizing to complementary DNA and RNAs, bind and stabilize DNA secondary structures. Herein, we illustrate the design and synthesis of PNA-like scaffolds by incorporating five-membered thiazole rings as modified bases instead of nucleobases and their subsequent effects on gene regulation by biophysical and in vitro assays. A thiazole-modified PNA trimer selectively recognizes c-MYC G-quadruplex (G4) DNA over other G4s and duplex DNA. It displays a high stabilization potential for the c-MYC G4 DNA and shows remarkable fluorescence enhancement with the c-MYC G4. It is flexible enough to bind at 5' and 3' ends as well as in the groove region of c-MYC G4. Furthermore, the PNA trimer easily permeates the cellular membrane and suppresses c-MYC mRNA expression in HeLa cells by targeting the promoter G4. This study illuminates modified PNAs as flexible molecular tools for selective targeting of noncanonical nucleic acids and modulating gene function.

Substituent effect of benzyl moiety in nitroquinoxaline small molecules upon DNA binding: Cumulative destacking of DNA nucleobases leading to histone eviction.

Cooperative disruption of Watson-Crick hydrogen bonds, as well as base-destacking, is shown to be triggered by a quinoxaline-based small molecule consisting of an N,N-dimethylaminopropyl tether, and a para-substituted benzyl moiety. This events lead to superstructure formation and DNA condensation as evident from biophysical experiments and classical molecular dynamics simulations. The DNA superstructure formation by mono-quinoxaline derivatives is highly entropically favored and predominantly driven by hydrophobic interactions. Furthermore, oversupercoiling of DNA and base-destacking cumulatively induces histone eviction from in-vitro assembled nucleosomes at lower micromolar concentrations implicating biological relevance. The DNA structural modulation and histone eviction capacity of the benzyl para-substituents are in the order: -I > -CF3> -Br > -Me > -OMe > -OH, which is largely guided by the polarity of benzyl para-substituent and the resulting molecular topology. The most hydrophobic derivative 3c with para-iodo benzyl moiety causes maximal disruption of base pairing and generation of superstructures. Both these events gradually diminish as the polarity of the benzyl para-substituent increases. On the other hand, quinoxaline derivatives having heterocyclic ring instead of benzyl ring, or in the absence of N,N-dimethylamino head-group, is incapable of inducing any DNA structural change and histone eviction. Further, the quinoxaline compounds displayed potent anticancer activities against different cancer cell lines which directly correlates with the hydrophobic effects of the benzyl para-substituents. Overall, the present study provides new insights into the mechanistic approach of DNA structural modulation driven histone eviction guided by the hydrophobicity of synthesized compounds leading to cellular cytotoxicity towards cancer cells.

Harnessing Noncovalent Interactions for a Directed Evolution of a Six-Component Molecular Crystal.

Building up on weak orthogonal interactions in supramolecular chemistry, a six-component crystal is designed. Using five distinctly different noncovalent forces, namely, hydrogen bonding, halogen bonding, cation-π, anion-π, and ion-pair interactions, three six-component crystals were designed with crown-ether (I), thiourea (II), 2,3,5,6-tetrafluoro-1,4-dibromobenzene (III), lone-pair donating anion (IV), ammonium cation (V), and electron-rich aromatic ring (VI). The M06-2X functional which is highly suitable in describing other weak interactions fails for ion-pairs. Tuned range-separated (RS)-DFT calculations are found to be capable in describing the ionic interactions in molecular solids. Molecular dynamics simulations show that the predicted multicomponent crystals are stable at room temperature and reducing the ionic charges for the ion-pairs destabilizes them. The strong electrostatic interactions between the three ion-pairs, NH4+···ClO4-, NH4+···HSO4-, and NH4+···HCO3- is the primary driving force for the stabilization of the six-component crystal. Using a hybrid of strong and weak intermolecular interactions, one may generate exotic molecular complexity like n-component crystals.

Molecular Mechanism for the Self-Supported Synthesis of Graphitic Carbon Nitride from Urea Pyrolysis.

Quantum chemical calculations combined with kinetic Monte Carlo simulations are performed to decipher the kinetics for the one-pot synthesis of two-dimensional graphitic carbon nitride (g-C3N4) from urea pyrolysis. Two mechanisms are considered, one involving ammelide as the intermediate compound and the other considering cyanuric acid. Different grid growing patterns are investigated, and the size, shape, and density of the grids as well as the number and position of the defects are evaluated. We find that the mechanistic pathway involving ammelide is preferred. Larger g-C3N4 grids with lower density are achieved when the rate constant for melon growing is inversely proportional to the number of local reaction sites, while nearly filled smaller grids are obtained in the opposite scenario. Larger defects appear at the grid periphery while smaller holes appear throughout the grid. The synthesis of extended g-C3N4 structures is favored if the g-C3N4 growing propensity is directly proportional to the number of reaction sites.

Disentangling the liquid phase exfoliation of two-dimensional materials: an "in silico" perspective.

Liquid Phase Exfoliation (LPE) is one of the most successful synthetic roots for the preparation of two-dimensional (2D) materials from their bulk counterparts. In recent years, significant progress has been accomplished for the development and modification of LPE techniques. However, precise identification of the hierarchical steps of the molecular mechanism of LPE remains to some extent elusive. Additionally, the a priori choice of suitable solvents for successful exfoliation and dispersion of various layered materials poses a challenge for both academia and industry. Computational methods, particularly Molecular Dynamics (MD) simulations with classical force-fields have contributed a great deal towards the understanding of the underlying mechanism of LPE, providing remarkable insights into the molecular-level details of the solvent-material interactions at the nanoscale and predicting "good" and "bad" solvents for exfoliation as well as stabilization of the dispersed state. With an intention to build up a unified understanding, in this perspective article, we summarize the recent advancements of molecular simulation techniques employed to decipher the mechanism of LPE, pointing out the key features of molecular interactions and identifying several thermodynamic parameters governing the phenomena. In addition, we outline the necessary characteristics of solvent molecules, essential for their use as "good" solvents towards LPE. Also, we highlight the limitations of simulation methods for the modelling of LPE. We believe that this article will be beneficial for the selection of solvents for the synthesis of novel 2D materials via LPE and will also provide a comprehensive view to computational material scientists towards the development of novel simulation protocols for investigating and analysing such complex molecular events.

Delicate Balance of Non-Covalent Forces Govern the Biocompatibility of Graphitic Carbon Nitride towards Genetic Materials.

Despite a plethora of suggested technological and biomedical applications, the nanotoxicity of two-dimensional (2D) graphitic carbon nitride (g-C3 N4 ) towards biomolecules remains elusive. To address this issue, we employ all-atom classical molecular dynamics simulations and investigate the interactions between nucleic acids and g-C3 N4 . It is revealed that, toxicity is modulated through a subtle balance between electrostatic and van der Waals interactions. When the exposed nucleobases interact through predominantly short-ranged van der Waals and π-π stacking interactions, they get deviated from their native disposition and adsorb on the surface, leading to loss of self-stacking and intra-quartet H-bonding along with partial disruption of the native structure. In contrast, for the interaction with double-stranded structures of both DNA and RNA, long-range electrostatics govern the adsorption phenomena since the constituent nucleobases are relatively concealed and wrapped, thereby resulting in almost complete preservation of the nucleic acid structures. Construction of free energy landscapes for lateral translation of adsorbed nucleic acids suggests decent targeting specificity owing to their restricted movement on g-C3 N4 . The release times of nucleic acids adsorbed through predominant electrostatics are significantly less than those adsorbed through stacking with the surface. It is therefore proposed that g-C3 N4 would induce toxicity towards any biomolecule having bare residues available for strong van der Waals and π-π stacking interactions relative to those predominantly interacting through electrostatics.

Screening two dimensional materials for the transportation and delivery of diverse genetic materials.

In spite of several reports of graphene and other 2D materials concerning their capacity for biomolecular adsorption and delivery, recent toxicity evaluations found them to be nanotoxic toward different biomolecules, especially nucleic acids. Therefore, there is urgent demand for the synthesis of 2D materials exhibiting biocompatible and non-nanotoxic features. In this article, employing classical molecular dynamics simulations, we provide a benchmarking of h2D-C2N, graphene and hexagonal boron nitride (h-BN) toward the adsorption, preservation, targeting and delivery of various classes of nucleic acids namely single stranded DNA, double stranded natural as well as unnatural base substituted DNA and two different types of human telomeric guanine quadruplexes, all comprising different secondary structures. Our simulations reveal that, while h2D-C2N preserves the structures of most of the nucleic acids, graphene and h-BN disrupt them through strong π-π stacking with aromatic nucleobases. Interestingly, for the first time we identified a 'quartet-by-quartet' disruption mechanism of guanine quadruplexes, but only on graphene and h-BN. The lateral diffusion of adsorbed nucleic acids over C2N is restricted unlike that over both graphene and h-BN, thereby increasing the targeting efficacy for C2N. Modeling of the delivery phenomena suggests orders of magnitude longer release times from graphene and h-BN compared to C2N, thereby demonstrating the preferential suitability of C2N for all the hierarchical steps of nucleic acid transportation.

Gauging the Nanotoxicity of h2D-C2N toward Single-Stranded DNA: An in Silico Molecular Simulation Approach.

Recent toxicological assessments of graphene, graphene oxides, and some other two-dimensional (2D) materials have shown them to be substantially toxic at the nanoscale, where they inhibit and eventually disrupt biological processes. These shortfalls of graphene and analogs have resulted in a quest for novel biocompatible 2D materials with minimum cytotoxicity. In this article, we demonstrate C2N (h2D-C2N), a newly synthesized 2D porous graphene analog, to be non-nanotoxic toward genetic materials from an "in-silico" point of view through sequence-dependent binding of different polynucleotide single-stranded DNA (ssDNA) onto it. The calculated binding energy of nucleobases and the free energy of binding of polynucleotides follow the common trait, cytosine > guanine > adenine > thymine, and are well within the limits of physisorption. Ab-initio simulations completely exclude the possibility of any chemical reaction, demonstrating purely noncovalent binding of nucleobases with C2N through a crucial interplay between hydrogen bonding and π-stacking interactions with the surface. Further, we show that the extent of distortion inflicted upon ssDNA by C2N is negligible. Analysis of the density of states of the nucleobase-C2N hybrids confirms minimum electronic perturbation of the bases after adsorption. Most importantly, we demonstrate the potency of C2N in nucleic acid transportation via reversible binding of ssDNA. The plausible use of C2N as a template for DNA repair is illustrated through an example of C2N-assisted complementary ssDNA winding.

Exploring the effect of hydroxylic and non-hydroxylic solvents on the reaction of [VIVO(ß-diketonate)2] with 2-aminobenzoylhydrazide in aerobic and anaerobic conditions.

Refluxing [VIVO(ß-diketonate)2], namely [VIVO(acetylacetonate)2] and [VIVO(benzoylacetonate)2], separately with an equivalent or excess amount of 2-aminobenzoylhydrazide (ah) in laboratory grade (LG) CH3OH in aerobic conditions afforded non-oxidovanadium(iv) and oxidovanadium(v) complexes of the type [VIV(L1)2] (1), [VVO(L1)(OCH3)]2 (3) and [VIV(L2)2] (2), and [VVO(L2)(OCH3)] (4), respectively. (L1)2- and (L2)2- represent the dianionic forms of 2-aminobenzoylhydrazone of acetylacetone (H2L1) and benzoylacetone (H2L2), respectively, (general abbreviation, H2L), which was formed by the in situ condensation of ah with the respective coordinated [ß-diketonate] in medium-to-good yield. The yield of different resulting products was dependent upon the ratio of ah to [VIVO(ß-diketonate)2]. For example, the yield of 1 and 2 complexes increased significantly associated with a decrease in the amount of 3 and 4 with an increase in the molar ratio of ah. Upon replacing CH3OH by a non-hydroxylic solvent, LG CHCl3, the above reaction yielded only oxidovanadium(v) complexes of the type [VVO(L1)(OH)]2 (5), [VVO(L2)(OH)] (6) and [VO3(L)2] (7, 8) whereas, upon replacing CHCl3 by another non-hydroxylic solvent, namely LG CH3CN, only the respective [VO3(L)2] (7, 8) complex was isolated in 72-78% yield. However, upon performing the above reactions in the absence of air using dry CH3OH or dry CHCl3, only the respective [VIV(L)2] complex was obtained, suggesting that aerial oxygen was the oxidising agent and the type of pentavalent product formed was dependent upon the nature of solvent used. Complexes 3 and 4 were converted, respectively, to 7 and 8 on refluxing in LG CHCl3via the respective unstable complex 5 and 6. The DFT calculated change in internal energy (ΔE) for the reactions 2[VVO(L2)(OCH3)] + 2H2O → 2[VVO(L2)(OH)] + 2CH3OH and 2[VVO(L2)(OH)] → [VO3(L2)2] + H2O was, respectively, +3.61 and -7.42 kcal mol-1, suggesting that the [VVO(L2)(OH)] species was unstable and readily transformed to the stable [VO3(L2)2] complex. Upon one-electron reduction at an appropriate potential, each of 7 and 8 generated mixed-valence [(L)VVO-(µ-O)-OVIV(L)]- species, which showed valence-delocalisation at room temperature and localisation at 77 K. Some of the complexes showed a wide range of toxicity in a dose-dependent manner against lung cancer cells comparable with that observed with cis-platin.

Controlling electronic effects and intermolecular packing in contorted polyaromatic hydrocarbons (c-PAHs): towards high mobility field effect transistors.

We have investigated the electronic and charge transport properties of two regioisomeric contorted polyaromatic hydrocarbons at the molecular level as well as in the crystalline state. Electron and hole transport is studied on the basis of an incoherent charge hopping model through DFT calculations. For trifluro-dibenzoperylene (CF3-DBP, ), which crystallizes as a herringbone network, the computed drift hole and electron mobilities are 0.234 and 0.008 cm(2) V(-1) S(-1), respectively. The greater hole mobility in the DBP crystal (µh/µe = 29) can be rationalized by its lower hole reorganization energy and higher hole transfer integral simultaneously. These calculations for the pristine DBP crystal differ from recent experiments indicating its preferential electron conductivity. This might be attributed to the interaction of the molecules with the gold source/drain electrodes. Its second regioisomer, , having a HOMO-LUMO gap of 3.2 eV and thus expectedly inefficient, can be converted into an effective OFET material by replacing the Ph-CF3 groups by oxo groups (>C[double bond, length as m-dash]O) in the 9 and 10 positions (9,10-dioxotribenzopyrene, ). has a suitable HOMO-LUMO gap of 2.18 eV. This bowl-shaped molecule is predicted to pack in a stacked orientation with preferential concaveconcave pairs having a short intermolecular distance of 4.15 Å and identical inter-chromophoric electron/hole coupling (th ∼ te). This creates an ambipolar charge transport behavior in . Clearly, fine tuning the structure-property relationship opens up the possibility of implanting tailored OFET properties in the existing library of molecules.