Understanding Self-Assembly and Molecular Packing in Methylcellulose Aqueous Solutions Using Multiscale Modeling and Simulations.

We present a multiscale molecular dynamics (MD) simulation study on self-assembly in methylcellulose (MC) aqueous solutions. First, using MD simulations with a new coarse-grained (CG) model of MC chains in implicit water, we establish how the MC chains self-assemble to form fibrils and fibrillar networks and elucidate the MC chains' packing within the assembled fibrils. The CG model for MC is extended from a previously developed model for unsubstituted cellulose and captures the directionality of H-bonding interactions between the -OH groups. The choice and placement of the CG beads within each monomer facilitates explicit modeling of the exact degree and position of methoxy substitutions in the monomers along the MC chain. CG MD simulations show that with increasing hydrophobic effect and/or increasing H-bonding strength, the commercial MC chains (with degree of methoxy substitution, DS, ∼1.8) assemble from a random dispersed configuration into fibrils. The assembled fibrils exhibit consistent fibril diameters regardless of the molecular weight and concentration of MC chains, in agreement with past experiments. Most MC chains' axes are aligned with the fibril axis, and some MC chains exhibit twisted conformations in the fibril. To understand the molecular driving force for the twist, we conduct atomistic simulations of MC chains preassembled in fibrils (without any chain twists) in explicit water at 300 and 348 K. These atomistic simulations also show that at DS = 1.8, MC chains adopt twisted conformations, with these twists being more prominent at higher temperatures, likely as a result of shielding of hydrophobic methyl groups from water. For MC chains with varying DS, at 348 K, atomistic simulations show a nonmonotonic effect of DS on water-monomer contacts. For 0.0 < DS < 0.6, the MC monomers have more water contacts than at DS = 0.0 or DS > 0.6, suggesting that with few methoxy substitutions, the MC chains are effectively hydrophilic, letting the water molecules diffuse into the fibril to participate in H-bonds with the MC chains' remaining -OH groups. At DS > 0.6, the MC monomers become increasingly hydrophobic, as seen by decreasing water contacts around each monomer. We conclude based on the atomistic observations that MC chains with lower degrees of substitutions (DS ≤ 0.6) should exhibit solubility in water over broader temperature ranges than DS ∼ 1.8 chains.

Synergistic Role of Temperature and Salinity in Aggregation of Nonionic Surfactant-Coated Silica Nanoparticles.

The adsorption of nonionic surfactants onto hydrophilic nanoparticles (NPs) is anticipated to increase their stability in aqueous medium. While nonionic surfactants show salinity- and temperature-dependent bulk phase behavior in water, the effects of these two solvent parameters on surfactant adsorption and self-assembly onto NPs are poorly understood. In this study, we combine adsorption isotherms, dispersion transmittance, and small-angle neutron scattering (SANS) to investigate the effects of salinity and temperature on the adsorption of pentaethylene glycol monododecyl ether (C12E5) surfactant on silica NPs. We find an increase in the amount of surfactant adsorbed onto the NPs with increasing temperature and salinity. Based on SANS measurements and corresponding analysis using computational reverse-engineering analysis of scattering experiments (CREASE), we show that the increase in salinity and temperature results in the aggregation of silica NPs. We further demonstrate the non-monotonic changes in viscosity for the C12E5-silica NP mixture with increasing temperature and salinity and correlate the observations to the aggregated state of NPs. The study provides a fundamental understanding of the configuration and phase transition of the surfactant-coated NPs and presents a strategy to manipulate the viscosity of such dispersion using temperature as a stimulus.

Effects of solvent conditions on the self-assembly of heterotrimeric collagen-like peptide (CLP) triple helices: a coarse-grained simulation study.

We perform coarse-grained (CG) molecular dynamics (MD) simulations to investigate the self-assembly of collagen-like peptide (CLP) triple helices into fibrillar structures and percolated networks as a function of solvent quality. The focus of this study is on CLP triple helices whose strands are different lengths (i.e., heterotrimers), leading to dangling 'sticky ends'. These 'sticky ends' are segments of the CLP strands that have unbonded hydrogen-bonding donor/acceptor sites that drive heterotrimeric CLP triple helices to physically associate with one another, leading to assembly into higher-order structures. We use a validated CG model for CLP in implicit solvent and capture varying solvent quality through changing strength of attraction between CG beads representing the amino acids in the CLP strands. Our CG MD simulations show that, at lower CLP concentrations, CLP heterotrimers assemble into fibrils and, at higher CLP concentrations, into percolated networks. At higher concentrations, decreasing solvent quality causes (i) the formation of heterogeneous network structures with a lower degree of branching at network junctions and (ii) increases in the diameter of network strands and pore sizes. We also observe a nonmonotonic effect of solvent quality on distances between network junctions due to the balance between heterotrimer end-end associations driven by hydrogen bonding and side-side associations driven by worsening solvent quality. Below the percolation threshold, we observe that decreasing solvent quality leads to the formation of fibrils composed of multiple aligned CLP triple helices, while the number of 'sticky ends' governs the spatial extent (radius of gyration) of the assembled fibrils.

Polymer solution structure and dynamics within pores of hexagonally close-packed nanoparticles.

Using coarse-grained molecular dynamics simulations, we examine structure and dynamics of polymer solutions under confinement within the pores of a hexagonally close-packed (HCP) nanoparticle system with nanoparticle diameter fifty times that of the polymer Kuhn segment size. We model a condition where the polymer chain is in a good solvent (i.e., polymer-polymer interaction is purely repulsive and polymer-solvent and solvent-solvent interactions are attractive) and the polymer-nanoparticle and solvent-nanoparticle interactions are purely repulsive. We probe three polymer lengths (N = 10, 114, and 228 Kuhn segments) and three solution concentrations (1, 10, and 25%v) to understand how the polymer chain conformations and chain center-of-mass diffusion change under confinement within the pores of the HCP nanoparticle structure from those seen in bulk. The known trend of bulk polymer Rg2 decreasing with increasing concentration no longer holds when confined in the pores of HCP nanoparticle structure; for example, for the 114-mer, the HCP 〈Rg2〉 at 1%v concentration is lower than HCP 〈Rg2〉 at 10%v concentration. The 〈Rg2〉 of the 114-mer and 228-mer exhibit the largest percent decline going from bulk to HCP at the 1%v concentration and the smallest percent decline at the 25%v concentration. We also provide insight into how the confinement ratio (CR) of polymer chain size to pore size within tetrahedral and octahedral pores in the HCP arrangement of nanoparticles affects the chain conformation and diffusion at various concentrations. At the same concentration, the N = 114 has significantly more movement between pores than the N = 228 chains. For the N = 114 polymer, the diffusion between pores (i.e., inter-pore diffusion) accelerates the overall diffusion rate for the confined HCP system while for the N = 228 polymer, the polymer diffusion in the entire HCP is dominated by the diffusion within the tetrahedral or octahedral pores with minor contributions from inter-pore diffusion. These findings augment the fundamental understanding of macromolecular diffusion through large, densely packed nanoparticle assemblies and are relevant to research focused on fabrication of polymer composite materials for chemical separations, storage, optics, and photonics. We perform coarse-grained molecular dynamics simulations to understand structure and dynamics of polymer solutions under confinement within hexagonal close packed nanoparticles with radii much larger than the polymer chain's bulk radius of gyration.

Impact of collagen-like peptide (CLP) heterotrimeric triple helix design on helical thermal stability and hierarchical assembly: a coarse-grained molecular dynamics simulation study.

Collagen-like peptides (CLP) are multifunctional materials garnering a lot of recent interest from the biomaterials community due to their hierarchical assembly and tunable physicochemical properties. In this work, we present a computational study that links the design of CLP heterotrimers to the thermal stability of the triple helix and their self-assembly into fibrillar aggregates and percolated networks. Unlike homotrimeric helices, the CLP heterotrimeric triple helices in this study are made of CLP strands of different chain lengths that result in 'sticky' ends with available hydrogen bonding groups. These 'sticky' ends at one end or both ends of the CLP heterotrimer then facilitate inter-helix hydrogen bonding leading to self-assembly into fibrils (clusters) and percolated networks. We consider the cases of three sticky end lengths - two, four, and six repeat units - present entirely on one end or split between two ends of the CLP heterotrimer. We observe in CLP heterotrimer melting curves generated using coarse grained Langevin dynamics simulations at low CLP concentration that increasing sticky end length results in lower melting temperatures for both one and two sticky ended CLP designs. At higher CLP concentrations, we observe non-monotonic trends in cluster sizes with increasing sticky end length with one sticky end but not for two sticky ends with the same number of available hydrogen bonding groups as the one sticky end; this nonmonotonicity stems from the formation of turn structures stabilized by hydrogen bonds at the single, sticky end for sticky end lengths greater than four repeat units. With increasing CLP concentration, heterotrimers also form percolated networks with increasing sticky end length with a minimum sticky end length of four repeat units required to observe percolation. Overall, this work informs the design of thermoresponsive, peptide-based biomaterials with desired morphologies using strand length and dispersity as a handle for tuning thermal stability and formation of supramolecular structures.

Unraveling the Structure and Function of Melanin through Synthesis.

Melanin is ubiquitous in living organisms across different biological kingdoms of life, making it an important, natural biomaterial. Its presence in nature from microorganisms to higher animals and plants is attributed to the many functions of melanin, including pigmentation, radical scavenging, radiation protection, and thermal regulation. Generally, melanin is classified into five types-eumelanin, pheomelanin, neuromelanin, allomelanin, and pyomelanin-based on the various chemical precursors used in their biosynthesis. Despite its long history of study, the exact chemical makeup of melanin remains unclear, and it moreover has an inherent diversity and complexity of chemical structure, likely including many functions and properties that remain to be identified. Synthetic mimics have begun to play a broader role in unraveling structure and function relationships of natural melanins. In the past decade, polydopamine, which has served as the conventional form of synthetic eumelanin, has dominated the literature on melanin-based materials, while the synthetic analogues of other melanins have received far less attention. In this perspective, we will discuss the synthesis of melanin materials with a special focus beyond polydopamine. We will emphasize efforts to elucidate biosynthetic pathways and structural characterization approaches that can be harnessed to interrogate specific structure-function relationships, including electron paramagnetic resonance (EPR) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. We believe that this timely Perspective will introduce this class of biopolymer to the broader chemistry community, where we hope to stimulate new opportunities in novel, melanin-based poly-functional synthetic materials.

Combining simulations and experiments for the molecular engineering of multifunctional collagen mimetic peptide-based materials.

Assembling peptides allow the creation of structurally complex materials, where amino acid selection influences resulting properties. We present a synergistic approach of experiments and simulations for examining the influence of natural and non-natural amino acid substitutions via incorporation of charged residues and a reactive handle on the thermal stability and assembly of multifunctional collagen mimetic peptides (CMPs). Experimentally, we observed inclusion of charged residues significantly decreased the melting temperature of CMP triple helices with further destabilization upon inclusion of the reactive handle. Atomistic simulations of a single CMP triple helix in explicit water showed increased residue-level and helical structural fluctuations caused by the inclusion of the reactive handle; however, these atomistic simulations cannot be used to predict changes in CMP melting transition. Coarse-grained (CG) simulations of CMPs at experimentally relevant solution conditions, showed, qualitatively, the same trends as experiments in CMP melting transition temperature with CMP design. These simulations show that when charged residues are included electrostatic repulsions significantly destabilize the CMP triple helix and that an additional inclusion of a reactive handle does not significantly change the melting transition. Based on findings from both experiments and simulations, the sequence design was refined for increased CMP triple helix thermal stability, and the reactive handle was utilized for the incorporation of the assembled CMPs within covalently crosslinked hydrogels. Overall, a unique approach was established for predicting stability of CMP triple helices for various sequences prior to synthesis, providing molecular insights for sequence design towards the creation of bulk nanostructured soft biomaterials.

Anisotropic Synthetic Allomelanin Materials via Solid-State Polymerization of Self-Assembled 1,8-Dihydroxynaphthalene Dimers.

Melanosomes in nature have diverse morphologies, including spheres, rods, and platelets. By contrast, shapes of synthetic melanins have been almost entirely limited to spherical nanoparticles with few exceptions produced by complex templated synthetic methods. Here, we report a non-templated method to access synthetic melanins with a variety of architectures including spheres, sheets, and platelets. Three 1,8-dihydroxynaphthalene dimers (4-4', 2-4' and 2-2') were used as self-assembling synthons. These dimers pack to form well-defined structures of varying morphologies depending on the isomer. Specifically, distinctive ellipsoidal platelets can be obtained using 4-4' dimers. Solid-state polymerization of the preorganized dimers generates polymeric synthetic melanins while maintaining the initial particle morphologies. This work provides a new route to anisotropic synthetic melanins, where the building blocks are preorganized into specific shapes, followed by solid-state polymerization.

Self-assembly of amphiphilic polymers of varying architectures near attractive surfaces.

We use coarse-grained molecular dynamics simulations to investigate the assembly of A-B amphiphilic polymers near/on surfaces as a function of polymer architecture and surface attraction to the solvophobic B-block in the polymer. We study four polymer architectures: linear, bottlebrush with a backbone that is longer than each of the side chains, bottlebrush where the solvophobic backbone is similar in length to each of the side chains, and 'star-like' architectures where the backbone is significantly shorter than the side chain lengths. For each architecture and surface-B attraction, we quantify the assembled aggregate structure (i.e., aggregation number, domain shapes and sizes) and the chain conformations (i.e., components of the chain radius of gyration) on and away from the surface. For all the architectures and surface-B attraction strengths, the assembled structure away from the surface is similar to the assembly observed in bulk systems without surfaces. Near/on the surface, the assembled B-blocks form domains whose shapes and sizes are dependent on the surface-B attraction strength and the ability of the B-block in the polymer architecture to change conformations and pack on the surface. Domain sizes formed from linear and 'star-like' polymer architectures show the highest sensitivity to surface-B-block attraction strength, transitioning from hemispherical to disordered domains with increasing attraction strength. In contrast, bottlebrushes with long backbones and short side chains transition from hemispherical to striped to continuous domains with increasing surface-B attraction strength. Bottlebrushes with similar solvophobic backbone and side chain lengths form hemispherical domains that do not change significantly with the surface-B-block attraction strength. These computational results can guide experimentalists in their choices of surface chemistry and polymer architecture to achieve desired assembled domain shapes and sizes on the surface.

Computational Reverse-Engineering Analysis for Scattering Experiments on Amphiphilic Block Polymer Solutions.

In this paper, we present a computational reverse-engineering analysis for scattering experiments (CREASE) based on genetic algorithms and molecular simulation to analyze the structure within self-assembled amphiphilic polymer solutions. For a given input comprised of scattering intensity profiles and information about the amphiphilic polymers in solution, CREASE outputs the structure of the self-assembled micelles (e.g., core and corona diameters, aggregation number) as well as the conformations of the amphiphilic polymer chains in the micelle (e.g., blocks' radii of gyration, chain radii of gyration, monomer concentration profiles). First, we demonstrate CREASE's ability to reverse-engineer self-assembled nanostructures for scattering profiles obtained from molecular simulations (or in silico experiments) of generic coarse-grained bead-spring polymer chains in an implicit solvent. We then present CREASE's outputs for scattering profiles obtained from small-angle neutron scattering (SANS) experiments of poly(d-glucose carbonate) block copolymers in solution that exhibit assembly into spherical nanoparticles. The success of this method is demonstrated by its ability to replicate, quantitatively, the results from in silico experiments and by the agreement in micelle core and corona sizes obtained from microscopy of the in vitro solutions. The primary strength of CREASE is its ability to analyze scattering profiles without an off-the-shelf scattering model and the ability to provide chain and monomer level structural information that is otherwise difficult to obtain from scattering and microscopy alone.

Effect of Peptide Sequence on the LCST-Like Transition of Elastin-Like Peptides and Elastin-Like Peptide-Collagen-Like Peptide Conjugates: Simulations and Experiments.

Elastin-like polypeptides (ELPs) are thermoresponsive biopolymers that undergo an LCST-like phase transition in aqueous solutions. The temperature of this LCST-like transition, Tt , can be tuned by varying the number of repeat units in the ELP, sequence and composition of the repeat units, the solution conditions, and via conjugation to other biomacromolecules. In this study, we show how and why the choice of guest (X) residue in the VPGXG pentad repeat tunes the Tt of short ELPs, (VPGXG)4, in the free state and when conjugated to collagen-like peptides (CLPs). In experiments, the (VPGWG)4 chain (in short, WWWW) has a Tt < 278 K, while (VPGFG)4 or FFFF has a Tt > 353 K in both free ELP and ELP-CLP systems. The Tt for the FWWF ELP sequence decreases from being >353 K for free ELP to <278 K for the corresponding ELP-CLP system. The decrease in Tt upon conjugation to CLP has been shown to be due to the crowding of ELP chains that decreases the entropic loss upon ELP aggregation. Even though the net hydrophobicity of ELP has been reasoned to drive the Tt , the origins of lower Tt of WWWW compared to FFFF are unclear, as there is disagreement in hydrophobicity scales in how phenylalanine (F) compares to tryptophan (W). Motivated by these experimental observations, we use a combination of atomistic and coarse-grained (CG) molecular dynamics simulations. Atomistic simulations of free and tethered ELPs show that WWWW are more prone to acquire ß-turn structures than FFFF at lower temperatures. Also, the atomistically informed CG simulations show that the increased local stiffness in W than F due to the bulkier side chain in W compared to F, alone does not cause the shift in the transition of WWWW versus FFFF. The experimentally observed lower Tt of WWWW than FFFF is achieved in CG simulations only when the CG model incorporates both the atomistically informed local stiffness and stronger effective attractions localized at the W position versus the F position. The effective interactions localized at the guest residue in the CG model is guided by our atomistically observed increased propensity for ß-turn structure in WWWW versus FFFF and by past experimental work of Urry et al. quantifying hydrophobic differences through enthalpy of association for W versus F.

Molecular dynamics simulation study of linear, bottlebrush, and star-like amphiphilic block polymer assembly in solution.

In this study we investigate the effect of varying branched polymer architectures on the assembly of amphiphilic block polymers in solution using coarse-grained molecular dynamics simulations. We quantify assembly structure (e.g., aggregation number, assembly morphology, and micelle core size) and thermodynamics (e.g., unimer to micelle transition conditions) as a function of increasing solvophobicity of the solvophobic block in the copolymer for three broad categories of polymer architectures: linear, 'bottlebrush' (with many short side chains on a long backbone), and 'star-like' (with few long side chains on a short backbone). Keeping the total number of coarse-grained beads in each polymer (or polymer molecular weight) constant, as we go from either linear or 'star-like' to 'bottlebrush' polymer architectures, the micelle aggregation number and micelle core size decrease, and the solvophobicity required for assembly (i.e., transition solvophobicity) increases. This trend is linked to the topological/steric hinderance for making solvophobic bead contacts between neighboring polymers for the 'bottlebrush' polymer architecture compared to the linear or 'star-like' architectures. We are able to identify some universal trends in assembly by plotting the assembly structure and thermodynamics data as a function of branching parameter defined as the ratio of the branched chain to the linear chain radius of gyration in the unimer state, and the relative lengths of the backbone versus side chain. The results in this paper guide how one could manipulate the amphiphilic block polymer assembly structure and thermodynamics by choosing appropriate polymer architecture, block sequence, and composition.

Coarse-grained molecular dynamics simulations of α-1,3-glucan.

In this paper we present a computational study of aggregation in aqueous solutions of α-1,3-glucan captured using a coarse-grained (CG) model that can be extended to other polysaccharides. This CG model captures atomistic geometry (i.e., relative placement of the hydrogen bonding donors and acceptors within the monomer) of the α-1,3-glucan monomer, the directional interactions due to the donor-acceptor hydrogen bonds, and their effect on aggregation of multiple α-1,3-glucan chains without the extensive computational resources needed for simulations with atomistic models. Using this CG model, we conduct molecular dynamics simulations to assess the effect of varying α-1,3-glucan chain length and hydrogen bond interaction strengths on the aggregation of multiple chains at finite concentrations in implicit solvent. We quantify the hydrogen bonding strength needed for multiple chains to aggregate, the distribution of inter- and intra-chain hydrogen bonds within the aggregate and in some cases, the shapes of the aggregate. We also explore the effect of substitution/silencing of some randomly selected or specific hydrogen bonding sites in the chain on the aggregation and aggregate structure. In the unmodified α-1,3-glucan solution, the inter-chain hydrogen bonds cause the chains to aggregate into sheets. Random silencing of hydrogen bonding donor sites only increases the hydrogen bond strength needed for aggregation but retains the same aggregate structure as the unmodified chains. Specific silencing of the hydrogen-bonding site on the C6 carbon leads to the chains aggregating into planar sheets that then fold over to form hollow cylinders at intermediate hydrogen bond strength - 4.7 to 5.3 kcal mol-1. These cylindrical aggregates assemble end-to-end to form larger aggregates at higher hydrogen bond strengths.

Macromolecular 'size' and 'hardness' drives structure in solvent-swollen blends of linear, cyclic, and star polymers.

In this paper, we apply molecular simulation and liquid state theory to uncover the structure and thermodynamics of homopolymer blends of the same chemistry and varying chain architecture in the presence of explicit solvent species. We use hybrid Monte Carlo (MC)/molecular dynamics (MD) simulations in the Gibbs ensemble to study the swelling of ∼12 000 g mol-1 linear, cyclic, and 4-arm star polystyrene chains in toluene. Our simulations show that the macroscopic swelling response is indistinguishable between the various architectures and matches published experimental data for the solvent annealing of linear polystyrene by toluene vapor. We then use standard MD simulations in the NPT ensemble along with polymer reference interaction site model (PRISM) theory to calculate effective polymer-solvent and polymer-polymer Flory-Huggins interaction parameters (χeff) in these systems. As seen in the macroscopic swelling results, there are no significant differences in the polymer-solvent and polymer-polymer χeff between the various architectures. Despite similar macroscopic swelling and effective interaction parameters between various architectures, the pair correlation function between chain centers-of-mass indicates stronger correlations between cyclic or star chains in the linear-cyclic blends and linear-star blends, compared to linear chain-linear chain correlations. Furthermore, we note striking similarities in the chain-level correlations and the radius of gyration of cyclic and 4-arm star architectures of identical molecular weight. Our results indicate that the cyclic and star chains are 'smaller' and 'harder' than their linear counterparts, and through comparison with MD simulations of blends of soft spheres with varying hardness and size we suggest that these macromolecular characteristics are the source of the stronger cyclic-cyclic and star-star correlations.

Effect of oligonucleic acid (ONA) backbone features on assembly of ONA-star polymer conjugates: a coarse-grained molecular simulation study.

Understanding the impact of incorporating new physical and chemical features in oligomeric DNA mimics, termed generally as "oligonucleic acids" (ONAs), on their structure and thermodynamics will be beneficial in designing novel materials for a variety of applications. In this work, we conduct coarse-grained molecular simulations of ONA-star polymer conjugates with varying ONA backbone flexibility, ONA backbone charge, and number of arms in the star polymer at a constant ONA strand volume fraction to elucidate the effect of these design parameters on the thermodynamics and assembly of multi-arm ONA-star polymer conjugates. We quantify the thermo-reversible behavior of the ONA-star polymer conjugates by quantifying the hybridization of the ONA strands in the system as a function of temperature (i.e. melting curve). Additionally, we characterize the assembly of the ONA-star polymer conjugates by tracking cluster formation and percolation as a function of temperature, as well as cluster size distribution at temperatures near the assembly transition region. The key results are as follows. The melting temperature (Tm) of the ONA strands decreases upon going from a neutral to a charged ONA backbone and upon increasing flexibility of the ONA backbone. Similar behavior is seen for the assembly transition temperature (Ta) with varying ONA backbone charge and flexibility. While the number of arms in the ONA-star polymer conjugate has a negligible effect on the ONA Tm in these systems, as the number of ONA-star polymer arms increase, the assembly temperature Ta increases and local ordering in the assembled state improves. By understanding how factors like ONA backbone charge, backbone flexibility, and ONA-star polymer conjugate architecture impact the behavior of ONA-star polymer conjugate systems, we can better inform how the selection of ONA chemistry will influence resulting ONA-star polymer assembly.

Effect of conjugation on phase transitions in thermoresponsive polymers: an atomistic and coarse-grained simulation study.

Using atomistic and coarse-grained molecular dynamics (MD) simulations, we explain the shifts in lower critical solution temperature (LCST)-like phase transitions exhibited by elastin-like peptides (ELPs) upon conjugation to other macromolecules (e.g. collagen-like peptides or CLPs). First, using atomistic simulations, we study ELP oligomers with the sequence (VPGFG)6 in explicit water, and characterize the LCST-like transition temperature as one at which the ELP oligomers undergo a change in "hydration state". In agreement with past experimental observations of Luo and Kiick, upon anchoring ELP oligomers to a point to mimic ELP oligomers conjugated to another macromolecule, there is an apparent slight shift in the transition temperature to lower values compared to free (unconjugated) ELP oligomers. However, these atomistic simulations are limited to small systems of short ELPs, and as such do not capture the multiple chain aggregation/phase separation observed in experiments of ELPs. Therefore, we utilize phenomenological coarse-grained (CG) MD simulations to probe how conjugating a block of generic-LCST polymer to another rigid unresponsive macromolecular block impacts the transition temperatures at concentrations and length scales larger than atomistic simulations. We find that when multiple LCST polymer chains are conjugated to a rigid unresponsive polymer block, the increased local crowding of the LCST polymers shifts the transition marked by onset of chain aggregation to smaller effective polymer-polymer attraction energies compared to the free LCST polymer chains. The driving force needed for aggregation is reduced in the conjugates compared to free LCST polymer due to reduction in the loss of polymer configurational entropy upon aggregation.

Dispersing Zwitterions into Comb Polymers for Nonviral Transfection: Experiments and Molecular Simulation.

Polymer-based gene delivery vehicles benefit from the presence of hydrophilic groups that mitigate the inherent toxicity of polycations and that provide tunable polymer-DNA binding strength and stable complexes (polyplexes). However, hydrophilic groups screen charge, and as such can reduce cell uptake and transfection efficiency. We report the effect of embedding zwitterionic sulfobetaine (SB) groups in cationic comb polymers, using a combination of experiments and molecular simulations. Ring-opening metathesis polymerization (ROMP) produced comb polymers with tetralysine (K4) and SB pendent groups. Dynamic light scattering, zeta potential measurements, and fluorescence-based experiments, together with coarse-grained molecular dynamics simulations, described the effect of SB groups on the size, shape, surface charge, composition, and DNA binding strength of polyplexes formed using these comb polymers. Experiments and simulations showed that increasing SB composition in the comb polymers decreased polymer-DNA binding strength, while simulations indicated that the SB groups distributed throughout the polyplex. This allows polyplexes to maintain a positive surface charge and provide high levels of gene expression in live cells. Notably, comb polymers with nearly 50 mol % SB form polyplexes that exhibit positive surface charge similarly as polyplexes formed from purely cationic comb polymers, indicating the ability to introduce an appreciable amount of SB functionality without screening surface charge. This integrated simulation-experimental study demonstrates the effectiveness of incorporating zwitterions in polyplexes, while guiding the design of new and effective gene delivery vectors.

Effect of backbone chemistry on hybridization thermodynamics of oligonucleic acids: a coarse-grained molecular dynamics simulation study.

In this paper we study how varying oligonucleic acid backbone chemistry affects the hybridization/melting thermodynamics of oligonucleic acids. We first describe the coarse-grained (CG) model with tunable parameters that we developed to enable the study of both naturally occurring oligonucleic acids, such as DNA, and their chemically-modified analogues, such as peptide nucleic acids (PNAs) and locked nucleic acids (LNAs). The DNA melting curves obtained using such a CG model and molecular dynamics simulations in an implicit solvent and with explicit ions match with the melting curves obtained using the empirical nearest-neighbor models. We use these CG simulations to then elucidate the effect of backbone flexibility, charge, and nucleobase spacing along the backbone on the melting curves, potential energy and conformational entropy change upon hybridization and base-pair hydrogen bond residence time. We find that increasing backbone flexibility decreases duplex thermal stability and melting temperature mainly due to increased conformational entropy loss upon hybridization. Removing charges from the backbone enhances duplex thermal stability due to the elimination of electrostatic repulsion and as a result a larger energetic gain upon hybridization. Lastly, increasing nucleobase spacing decreases duplex thermal stability due to decreasing stacking interactions that are important for duplex stability.

Wetting-Dewetting and Dispersion-Aggregation Transitions Are Distinct for Polymer Grafted Nanoparticles in Chemically Dissimilar Polymer Matrix.

Simulations and experiments are conducted on mixtures containing polymer grafted nanoparticles in a chemically distinct polymer matrix, where the graft and matrix polymers exhibit attractive enthalpic interactions at low temperatures that become progressively repulsive as temperature is increased. Both coarse-grained molecular dynamics simulations, and X-ray scattering and neutron scattering experiments with deuterated polystyrene (dPS) grafted silica and poly(vinyl methyl ether) PVME matrix show that the sharp phase transition from (mixed) dispersed to (demixed) aggregated morphologies due to the increasingly repulsive effective interactions between the blend components is distinct from the continuous wetting-dewetting transition. Strikingly, this is unlike the extensively studied chemically identical graft-matrix composites, where the two transitions have been considered to be synonymous, and is also unlike the free (ungrafted) blends of the same graft and matrix homopolymers, where the wetting-dewetting is a sharp transition coinciding with the macrophase separation.

Effect of Hydrophobic and Hydrophilic Surfaces on the Stability of Double-Stranded DNA.

DNA hybridization is the foundation for numerous technologies like DNA origami and DNA sensing/microarrays. Using molecular simulations, enhanced-sampling methods, and free-energy calculations, we show the effects of hydrophilic and hydrophobic surfaces on DNA hybridization. Hydrophilic surfaces compete with terminal bases' H-bonds but stabilize central base stacking. Hydrophobic surfaces strengthen terminal H-bonds but destabilize central base stacking. Regardless of surface chemistry, for terminal bases, melting proceeds through breaking H-bonds, followed by unstacking from the neighboring base. For central bases in bulk or near hydrophobic surfaces, melting proceeds by disruption of H-bonds, followed by unstacking, whereas on hydrophilic surfaces, unstacking from one neighboring base precedes complete disruption of the H-bonds, followed by unstacking from the second neighboring base. Kinetic barriers to melting and hybridization show that the central bases melt rapidly near hydrophobic surfaces, which can accelerate conformational searching and thereby accelerate folding into the desired conformation.