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The design of nanoparticles (NPs) that respond to external stimuli like pH, temperature, and electric or magnetic fields has found immense interest in various fields of nanotechnology like nanomedicine, drug delivery, and cancer therapy. Nanoparticles grafted with polymeric ligands have been extensively used as building blocks in the directed self assembly of nanoparticles. These moieties not only assemble into various morphologies but also respond to a wide range of external stimuli. In this work, we have used coarse grained molecular dynamics simulations to understand the stimuli-responsive behavior of assemblies of NPs grafted with oppositely charged polyions (PGNs) in the presence of salt and polyelectrolytes. At low grafting density, a transformation from ring morphology to form dimers/strings/dispersed NPs was observed upon addition of divalent/trivalent salts. NPs grafted with longer grafts showed higher stability to remain as rings compared to shorter grafts. The change in NP morphology was a direct consequence of preferential interaction of the polyaion grafts with the oppositely charged salt ions compared to the oppositely charged grafts on the NPs. At fixed salt valency, the size of the salt ion, concentration and molecular connectivity played a crucial role in the stimuli responsive behavior of polyion grafted NPs in solutions. Further, in the presence of polyelectrolytes, these transitions occurred at lower monomer valency due to the stronger electrostatic interactions between the grafted chains and oppositely charged free polyelectrolytes in solutions. Disordered and ordered aggregates assemblies formed at higher grafting density were broken into smaller NP assemblies in the presence of salt. Drug encapsulation studies in the presence of salt and polyelectrolytes were performed on model drug moieties in order to demonstrate the potential use of the modelled stimuli responsive nanoparticle assemblies in drug delivery applications.

DNA mediated directed self assembly of gold nanoparticles (AuNPs) has garnered immense interest due to its ability to precisely control supramolecular assemblies. Most experimental works have relied on utilizing the complementary interactions between the DNA strands to drive the self assembly of AuNPs grafted with DNA strands. In the present work, we have leveraged DNA-peptide interactions to tune the self assembly and stimuli responsive behavior of AuNPs grafted with single stranded DNA (ssDNA) and poly-L-lysine (PLL) chains. Our findings show that the electrostatic interactions between the negatively charged ssDNA grafts and positively charged PLL grafts, drive the self assembly of AuNPs of different sizes into 3D nanostructures. The transmission electron micrographs confirm that the smaller AuNPs grafted with PLL chains form a corona around the large AuNPs grafted with ssDNA like the petals around a flowery core to drive aggregation of large AuNPs. When the grafting of ssDNA and PLL on the different sized AuNPs is swapped, aggregates of large AuNPs mediated by the ssDNA grafts on the smaller AuNPs were observed. The presence of excess ssDNA/PLL chains in solutions affected both the morphology and the mechanism of aggregate formation. Coarse-grain molecular dynamics simulations qualitatively match the experimental findings and provided a scientific rationale to the above findings highlighting the role of chain entropy, molecular connectivity, and charge correlations on the self assembly of AuNPs.

Cationic helical peptides play a crucial role in applications such as anti-microbial and anti-cancer activity. The activity of these peptides directly correlates with their helicity. In this study, we have performed extensive all-atom molecular dynamics simulations of 25 Lysine-Leucine co-polypeptide sequences of varying charge density ( λ ) and patterns. Our findings showed that an increase in the charge density on the peptide leads to a gradual decrease in the helicity up to a critical charge density λ c . Beyond, λ c a complete helix to coil transition was observed. The decrease in the helicity correlated with the increased number of water molecules in first solvation shell, solvent-exposed surface area, and a higher value of the radius of gyration of the peptide.

Protein folding is a very complex process and, so far, the mechanism of folding still intrigues the research community. Despite a large conformational space available (O(1047) for a 100 amino acid residue), most proteins fold into their native state within a very short time. While small proteins fold relatively fast (a few microseconds) large globular proteins may take as long as several milliseconds to fold. During the folding process, the protein synthesized in the ribosome is exposed to the crowded environment of the cell and is easily prone to misfolding and aggregation due to interactions with other proteins or biomacromolecules present within the cell. These large proteins, therefore, rely on chaperones for their folding and repair. Chaperones are known to have hydrophobic patchy domains that play a crucial role in shielding the protein against misfolding and disaggregation of aggregated proteins. In the current article, Monte Carlo simulations carried out in the framework of the hydrophobic–polar (H–P) lattice model indicate that hydrophobic patchy domains drastically reduce the inter-protein interactions and are efficient in disaggregating proteins. The effectiveness of the disaggregation depends on the size and distribution of these patches on the surface and also on the strength of the interaction between the protein and the surface. Further, our results indicate that when the patch is complementary to the exposed hydrophobic patch of the protein, protein disaggregation is accompanied by stabilization of the protein even relative to its bulk behavior due to favorable protein–surface interactions. We believe that these findings shed light on the role of the class of chaperones known as heat shock proteins (Hsps) on protein disaggregation and refolding.

Nanoparticle self-assembly in solution has gained immense interest due to the enhanced optical, chemical, magnetic, and electrical properties which manifest at the macroscale. Material properties in bulk are a direct consequence of the morphology of these nanoparticles in solutions. Precise control on the orientation, spatial arrangement, shape, size, composition, and control over the interactions of individual nanoparticles play a key role in enhancing their properties. While previous studies have used asymmetry in the nanoparticle and/or the use of linker grafts, nanoparticles grafted with polyelectrolyte grafts provide us a wide parameter space to control and tune their self-assembly in solutions. In this study, we have performed coarse-grained molecular dynamics simulations to understand the charge-driven self-assembly of spherical nanoparticles grafted with polyelectrolyte chains. Nanoparticles grafted with either positively or negatively charged polyelectrolyte chains self-assemble to different structures driven by both excluded volume and electrostatic interactions. Our study shows that by tuning the graft density, the chain length, and the charge density of the grafts, we could build and control a variety of self-assembled structures ranging from rings, dimers, strings, coil-like aggregates, and disordered-to-ordered aggregates.

[Image: see text] Mitochondrion, the powerhouse of the cells, has emerged as one of the unorthodox targets in anticancer therapy due to its involvement in several cellular functions. However, the development of small molecules for selective mitochondrial damage in cancer cells remained limited and less explored. To address this, in our work, we have synthesized a natural product inspired cyanine-based 3-methoxy pyrrole small molecule library by a concise strategy. This strategy involves Vilsmeier and Pd(0) catalyzed Suzuki cross-coupling reactions as key steps. The screening of the library members in HeLa cervical cancer cells revealed two new molecules that localized into subcellular mitochondria and damaged them. These small molecules perturbed antiapoptotic (Bcl-2/Bcl-xl) and pro-apoptotic (Bax) proteins to produce reactive oxygen species (ROS). Molecular docking studies showed that both molecules bind more tightly with the BH3 domain of Bcl-2 proteins compared to obatoclax (a pan-Bcl-2 inhibitor). These novel small molecules arrested the cell cycle in the G0/G1 phase, cleaved caspase-3/9, and finally prompted late apoptosis. This small molecule-mediated mitochondrial damage induced remarkably high cervical cancer cell death. These unique small molecules can be further explored as chemical biology tools and next-generation organelle-targeted anticancer therapy.

Donor–acceptor π-conjugated molecules with triphenylamine donor and different acceptor (H, cyano, and pyridinium) units with a double bond spacer were synthesized. These compounds exhibit bathochromic shifts in absorption and emission with an increase in the acceptor strength. Solvatochromic measurements in water reveal emitting states characterized by a polar nature with three distinct emission spectral regions from blue to red. Interestingly, binary mixtures of the stilbenes in acetonitrile and water gave white light emission. MD simulations of the admixtures reveal that the emission data directly correlate to the structural arrangements of the molecules driven by intermolecular and solvent interactions with micelle-like structural arrangements for one set and uniform homogenous mixing for the other two sets. Such a tunable emission strategy using simple structural siblings could offer great potential towards designing novel emitting systems.

Two AIE active α-cyanostilbene fluorophores substituted with octyl and hexadecyl chains were synthesized and examined for their absorption and fluorescence properties. The alkoxy substitution tunes the self-assembly in water and exhibits an intensity enhanced bathochromic shift, resulting in well-defined nanospheres with the formation of nice dendrimeric structures. Monte Carlo simulations validate our experimental observations and show the greater propensity of self-assembly formation for cyanostilbene containing a hexadecyl chain compared to a derivative containing an octyl chain. The results are substantiated by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and dynamic light scattering (DLS) studies. Such tunable self-assembled nanostructures seem promising for material and biological applications.

Our ability to predict the thermodynamic phase behavior of a material system is a direct reflection on our understanding of the relevant interactions. Voorn–Overbeek (VO) theory, which combines Flory–Huggins polymer mixing with Debye–Huckel electrostatics, has been used to describe the associative liquid–liquid phase separation phenomenon known as complex coacervation since the 1950s. The long-standing utility of this theory stems from its simplicity coupled with its apparent agreement with physical systems. VO theory has also served as the starting point for a large class of field theories that predict similar phase behaviors. Recent work using new hybrid simulation methods demonstrates novel coacervate-driven self-assembly is strongly affected by molecular details. Liquid state (LS) theory suggests there are fundamental reasons for this observation and that agreement between VO and experiment is fortuitous. It is hypothesized that VO/experimental matching is due to a cancellation of errors arising from ...

Reduced activity of enzymes upon immobilization is a major challenge for the industrial use of enzymes. Enzyme-surface interactions and interactions between the immobilized enzymes are thought of as primary reasons for the reduced activity. In the current paper, we study the thermal and structural stability of proteins on a patterned hydrophobic surface in the framework of a hydrophobic-polar lattice model. Our results indicate that, while a homogeneous hydrophobic surface denatures the proteins, carefully patterned surfaces can dramatically increase the stability of adsorbed proteins. The size, shape, and the distance between surface patterns play a significant role in determining the stability of proteins. When the spacing between the patterns is large, maximum stability is observed when the surface pattern is complementary to the exposed hydrophobic domain of the protein, while at smaller spacing, patterns with lower hydrophobicity stabilize the protein more compared to the complementary pattern. The findings from the paper can be rationalized to design novel enzyme-specific surfaces for immobilization with enhanced enzymatic activity.

Relative surface affinity between polymers and colloids is leveraged in many applications like filtration, adhesion, bio-sensing, etc. The surface affinity is governed by both enthalpic (relative interactions between the species and surface) and entropic (excluded volume) effects. Neglecting enthalpic effects, i.e. for purely athermal systems, entropy is the only driving force that controls the surface affinity of the species in a binary or multi-component mixture. Many intensive (relative size of colloids, chain length, equilibrium bond angle, chain flexibility) and extensive (confinement, temperature) factors can dramatically change the entropy of the system and thus enhance or decrease the surface affinities of the constituent species. In this article, we use coarse grained metropolis Monte Carlo simulations to delineate the role of these factors in entropic surface segregation in a binary mixture of polymers and colloids. At low number densities, excluded volume effects are negligible and we do not observe any entropic driven surface segregation. Therefore our system of interest is binary polymer–colloid mixtures at moderate to high number densities where excluded volume effects are predominant. Our results indicate that for flexible polymer chains, the surface is always enriched with colloids compared to polymers and this effect is enhanced for longer polymer chains. The configurational entropy of the flexible polymers is significantly reduced near the surface and therefore they prefer to stay in the bulk (away from the surface). However this behavior can be completely reversed by introducing a large degree of confinement and making the chains relatively rigid (less flexible). Our results show that polymer segregation of long stiff chains in slit pore geometry is driven by nematization near the surface while looping of polymers is observed under a large degree of confinement. We observe that for longer polymer chains with an equilibrium bond angle (θ = π), both confinement and chain stiffness enhance the surface segregation of polymers relative to colloids. However, the segregation behavior within a confinement is dependent on the polymer chain length. The surface segregation of polymers is dramatically decreased for chains with equilibrium bond angles independent of chain length and flexibility due to excluded volume effects and inefficient packing near the surface.

Aggregation-induced-emission luminogens (AIEgens) have gained considerable attention as interesting tools for several biomedical applications, especially for bioimaging due to their brightness and photostability. Numerous AIEgens have been developed for lighting up the subcellular organelles to understand their forms and functions not only healthy but also unhealthy states, such as in cancer cells. However, there is lack of easily synthesizable, biocompatible small molecules for illuminating mitochondria (powerhouses) inside cells. To address this issue, an easy and short synthesis of new biocompatible hydrazide-hydrazone-based small molecules with remarkable aggregation-induced emission (AIE) properties is described. These small-molecule AIEgens showed hitherto unobserved AIE properties due to dual intramolecular H-bonding confirmed by theoretical calculation, pH- and temperature-dependent fluorescence and X-ray crystallographic studies. Confocal microscopy showed that these AIEgens were internalized into the HeLa cervical cancer cells without showing any cytotoxicity. One of the AIEgens was tagged with a triphenylphosphine (TPP) moiety, which successfully localized in the mitochondria of HeLa cells in a selective way compared to L929 noncancerous fibroblast cells. These unique hydrazide-hydrazone-based biocompatible AIEgens can serve as powerful tools to illuminate multiple subcellular organelles to elucidate their forms and functions in cancer cells for next-generation biomedical applications.

Oppositely charged polyelectrolytes in aqueous solution can undergo associative phase separation into a liquid-like complex coacervate phase that is polyelectrolyte-rich and an aqueous supernatant phase that is polyelectrolyte-deficient. This same complex coacervation motif can be used to drive self-assembly of block copolyelectrolytes via electrostatic interactions and can be controlled using e.g. ionic strength, pH, temperature, and polymer architecture. While there has been a large amount of research studying this self-assembly, the ability of theory to accurately capture the disparate length scales that govern the appropriate physics is limited. This is especially true when the coacervates have a high charge density; examples include biopolymers such as heparin or DNA as well as synthetic polymers such as poly(styrenesulfonate) or poly(acrylic acid). We incorporate molecular-level Monte Carlo simulations into single chain in mean field simulations, leading to a multiscale, coarse-grained description o...

A simple fluorophore bearing a diethylaminocoumarin donor and a pyridinium acceptor was synthesized and utilized for the ultra-sensitive detection of heparin. The synthesized dicationic push-pull coumarin derivative emits strongly in the red-region (665 nm) and detects nanomolar concentrations (14.8 nM to 148 nM) of heparin in HEPES buffer and FBS serum solutions. The dication exhibits excellent fluorescence selectivity and sensitivity towards heparin over its analogues such as chondroitin 4-sulfate (CS), hyaluronic acid (HA) and dextran. This fluorescence assay is a convenient, sensitive method for monitoring heparin levels in biological samples. These findings were confirmed using coarse-grained Monte Carlo simulations, which provide us with a rationale for the selective binding of heparin.

The physical and chemical properties of solid substrates or surfaces critically influence the stability and activity of immobilized proteins such as enzymes. Reports of increased stability and activity of enzymes near/on surfaces as compared with those in solution abound; however, a mechanistic understanding is wanting. Simulations and experiments are used here to provide details toward such a mechanistic understanding. Experiments demonstrate increased activity of alcohol dehydrogenase (ADH) inside moderate hydrophilic mesopourous silica (SBA-15) pores but drastically decreased activity inside very hydrophilic NH2-SBA-15 surfaces as compared with that in solution. Also, the temperature stability of ADH was increased over that in solution when immobilized in a cavity with a mildly hydrophilic surface. Simulations confirm these experimental findings. Simulations calculated in the framework of a hydrophobic-polar (H-P) lattice model show increased thermal stability of a model 64-mer peptide on positive and zero curvature surfaces over that in solution. Peptides immobilized inside negative curvature cavities (concave) with hydrophilic surfaces exhibit increased stability only inside pores that are only 3-4 nm larger than the hydrodynamic radius of the peptide. Peptides are destabilized, however, when the surface hydrophilic character inside very small cavities/pores becomes large.

Preventing protein aggregation is of both biological and industrial importance. Interprotein interactions between the hydrophobic residues of the protein are known to be the major driving force for protein aggregation. In this article, we show how surface chemistry and curvature can be tuned to mitigate these interprotein interactions. Our results calculated in the framework of the Hydrophobic-Polar (HP) lattice model show that interprotein interactions can be drastically reduced by increasing the surface hydrophobicity to a critical value corresponding to the adsorption transition of the protein. At this value of surface hydrophobicity, proteins lose interprotein contacts to gain surface contacts, and thus the surface helps to reduce the interprotein interactions. Furthermore, we show that the adsorption of the proteins inside hydrophobic pores of optimal sizes are most efficient at both reducing interprotein contacts and simultaneously retaining most of the native contacts probably as a result of confinement-induced stabilization.

We study the effects of confinement and hydrophobicity of a spherical cavity on the structural and thermal stability of proteins in the framework of a hydrophobic-polar (HP) lattice model. We observe that a neutral confinement stabilizes the folded state of the protein by eliminating many of the open-chain conformations of the unfolded state. Hydrophobic confinement always destabilizes the protein because of protein-surface interactions. However, for moderate surface hydrophobicities, the protein remains stabilized relative to its state in free solution because of the dominance of entropic effects. These results are consistent with our experimental findings of (a) enhanced activity of alcohol dehydrogenase (ADH) when immobilized inside the essentially cylindrical pores of hydrophilic mesoporous silica (SBA-15) and (b) unaffected activity when immobilized inside weakly hydrophobic pores of methacrylate resin compared to its activity in free solution. In the same vein, our predictions are also consistent with the behavior of lysozyme and myoglobin in hydrophilic and hydrophobic SBA-15, which show qualitatively the same trends. Apparently, our results have validity across these very different enzymes, and we therefore suggest that confinement can be used to selectively improve enzyme performance.

Using computer simulations to model the folding of proteins into their native states is computationally expensive due to the extraordinarily low degeneracy of the ground state. In this paper, we develop an efficient way to sample these folded conformations using Wang Landau sampling coupled with the configurational bias method (which uses an unphysical "temperature" that lies between the collapse and folding transition temperatures of the protein). This method speeds up the folding process by roughly an order of magnitude over existing algorithms for the sequences studied. We apply this method to study the adsorption of intrinsically disordered hydrophobic polar protein fragments on a hydrophobic surface. We find that these fragments, which are unstructured in the bulk, acquire secondary structure upon adsorption onto a strong hydrophobic surface. Apparently, the presence of a hydrophobic surface allows these random coil fragments to fold by providing hydrophobic contacts that were lost in protein fragmentation.