Native-Based Dissipative Particle Dynamics Approach for α-Helical Folding.

We developed a dissipative particle dynamics (DPD) approach that captures polyalanine folding into a stable helical conformation. Within the proposed native-based approach, the DPD parameters are derived based on the contact map constructed from the molecular dynamics (MD) simulations. We show that the proposed approach reproduces the folding of polypeptides of various lengths, including bundle formation for sufficiently long polypeptides. The proposed approach also allows one to capture the folding of the helical segments of the lysozyme. With further development of computationally efficient native-based DPD approaches for folding, modeling of a range of biomaterials incorporating α-helical segments could be extended to time and length scales far beyond those accessible in molecular dynamics simulations.

Computational Design of Nanostructured Soft Interfaces: Focus on Shape Changes and Spreading of Cubic Nanogels.

Understanding the dynamics of gels at soft interfaces is vital for a range of applications, from biocatalysis and drug delivery to enhanced oil recovery applications. Herein, we use dissipative particle dynamics simulations to focus on the shape changes of a cubic nanogel as it adsorbs from the aqueous phase onto the oil-water interface, effectively acting as a compatibilizer. Upon adsorption at the interface, the hydrogel spreads over the interface, adopting various shapes depending on its size and cross-link density. We characterize these shapes by the shape anisotropy and an effective extent of spreading. We highlight the differences between these characteristics for cubic and spherical nanogels and show that the choice of the cubic shape over the spherical one results in a wider range of topographies that could be dynamically prescribed onto the soft interface due to the gels' adsorption. We first validate our model parameters with respect to the known experimental values for polyacrylamide (PAAm) gels and focus on spreading and shape changes of PAAm nanogels onto the oil-water interfaces. We then probe the behavior of active gels by changing an affinity of the polymer matrix for the solvent, which can be caused by the application of an external stimulus (light, temperature, or change in the chemical composition of solvent). Furthermore, we focus on the interactions between multiple gels placed at the liquid-liquid interface. We show that controlling the shapes and the clustering of the gels at the interfaces via variations in solvent quality result in tailoring the dynamics and topography of soft nanostructured interfaces. Hence, our findings provide insights into the design of soft active nanostructured interfaces with topographies controlled externally via solvent quality.

Designing Highly Thermostable Lysozyme-Copolymer Conjugates: Focus on Effect of Polymer Concentration.

Designing biomaterials capable of functioning in harsh environments is vital for a range of applications. Using molecular dynamics simulations, we show that conjugating lysozymes with a copolymer [poly(GMA- stat-OEGMA)] comprising glycidyl methacrylate (GMA) and oligo(ethylene glycol) methyl ether methacrylate (OEGMA) results in a dramatic increase of stability of these enzymes at high temperatures provided that the concentration of the copolymer in the close vicinity of the enzyme exceeds a critical value. In our simulations, we use triads containing the same ratio of GMA to OEGMA units as in our recent experiments (N. S. Yadavalli et al., ACS Catalysis, 2017, 7, 8675). We focus on the dynamics of the conjugate at high temperatures and on its structural stability as a function of the copolymer/water content in the vicinity of the enzyme. We show that the dynamics of phase separation in the water-copolymer mixture surrounding the enzyme is critical for the structural stability of the enzyme. Specifically, restricting water access promotes the structural stability of the lysozyme at high temperatures. We identified critical water concentration below which we observe a robust stabilization; the phase separation is no longer observed at this low fraction of water so that the water domains promoting unfolding are no longer formed in the vicinity of the enzyme. This understanding provides a basis for future studies on designing a range of enzyme-copolymer conjugates with improved stability.

Probing the ATP-induced conformational flexibility of the PcrA helicase protein using molecular dynamics simulation.

Helicases are enzymes that unwind double-stranded DNA (dsDNA) into its single-stranded components. It is important to understand the binding and unbinding of ATP from the active sites of helicases, as this knowledge can be used to elucidate the functionality of helicases during the unwinding of dsDNA. In this work, we investigated the unbinding of ATP and its effect on the active-site residues of the helicase PcrA using molecular dynamic simulations. To mimic the unbinding process of ATP from the active site of the helicase, we simulated the application of an external force that pulls ATP from the active site and computed the free-energy change during this process. We estimated an energy cost of ~85 kJ/mol for the transformation of the helicase from the ATP-bound state (1QHH) to the ATP-free state (1PJR). Unbinding led to conformational changes in the residues of the protein at the active site. Some of the residues at the ATP-binding site were significantly reoriented when the ATP was pulled. We observed a clear competition between reorientation of the residues and energy stabilization by hydrogen bonds between the ATP and active-site residues. We also checked the flexibility of the PcrA protein using a principal component analysis of domain motion. We found that the ATP-free state of the helicase is more flexible than the ATP-bound state.

Colloidal assembly by ice templating.

We investigate ice templating of aqueous dispersions of polymer coated colloids and crosslinkers, at particle concentrations far below that required to form percolated monoliths. Freezing the aqueous dispersions forces the particles into close proximity to form clusters, that are held together as the polymer chains coating the particles are crosslinked. We observe that, with an increase in the particle concentration from about 10(6) to 10(8) particles per ml, there is a transition from isolated single particles to increasingly larger clusters. In this concentration range, most of the colloidal clusters formed are linear or sheet like particle aggregates. Remarkably, the cluster size distribution for clusters smaller than about 30 particles, as well as the size distribution of linear clusters, is only weakly dependent on the dispersion concentration in the range that we investigate. We demonstrate that the main features of cluster formation are captured by kinetic simulations that do not consider hydrodynamics or instabilities at the growing ice front due to particle concentration gradients. Thus, clustering of colloidal particles by ice templating dilute dispersions appears to be governed only by particle exclusion by the growing ice crystals that leads to their accumulation at ice crystal boundaries.

Compact polar moieties induce lipid-water systems to form discontinuous reverse micellar phase.

The role of molecular interactions in governing lipid mesophase organization is of fundamental interest and has technological implications. Herein, we describe an unusual pathway for monoolein/water reorganization from a bicontinuous mesophase to a discontinuous reverse micellar assembly, directed by the inclusion of polar macromolecules. This pathway is very different from those reported earlier, wherein the Fd3m phase formed only upon addition of apolar oils. Experiments and molecular dynamics simulations indicate that hydrophilic ternary additives capable of inducing discontinuous phase formation must (i) interact strongly with the monoolein head group and (ii) have a compact molecular architecture. We present a detailed investigation that contrasts a monoolein-water system containing polyamidoamine (PAMAM) dendrons with one containing their linear analogs. The Fd3m phase forms only on the addition of PAMAM dendrons but not their linear analogs. Thus, the dendritic architecture of PAMAM plays an important role in determining lipid mesophase behavior. Both dendrons and their linear analogs interact strongly with monoolein through their amine groups. However, while linear polymers adsorb and spread on monoolein, dendrons form aggregates that interact with the lipid. Dendrons induce formation of an intermediate reverse hexagonal phase, which subsequently restructures into the Fd3m phase. Finally, we demonstrate that other additives with compact structures that are known to interact with monoolein, such as branched polyethylenimine and polyhedral silsesquioxane cages, also induce the formation of the Fd3m phase.

Characterization of conformation and interaction of gene delivery vector polyethylenimine with phospholipid bilayer at different protonation state.

Polyethylenimine (PEI) is a pH sensitive polymer possessing stretched and coiled conformation at low and high pH, respectively. It is an efficient gene delivery agent. Thus, the interaction of PEI with the biomembrane is very crucial to understand the gene delivery mechanism. In this report, we have investigated the structural properties of PEI and bilayer due to the interaction of PEI with lipid molecules. PEI has coil structure at high pH while at low pH it is elongated. The neutral PEI chain predominately settles itself at the bilayer water interface. We do not find any disruption or pore formation on the bilayer due to interaction of neutral PEI chain. PEI at low pH gets elongated due to electrostatic interaction between charges of the protonated sites. This protonated PEI chain interacts with bilayer membrane, which leads to formation of water/ion channel through the membrane. We have analyzed the structure of the channel and water dynamics along the channel.

Molecular dynamics simulation of phosphoric acid doped monomer of polybenzimidazole: a potential component polymer electrolyte membrane of fuel cell.

Phosphoric acid doped polybenzimidazole is promising electrolyte membranes for high temperature (100 °C and above) fuel cells. Proton conduction is governed by the amount of phosphoric acid content in the polymer membrane. In this present work, we perform molecular dynamics simulations on phosphoric acid doped 2-phenyl-1H,1'H-5,5'-bibenzo[d]imidazole (monomer unit of polybenzimidazole) to characterize the structural and dynamical properties at varying phosphoric acid content and temperature. From the structural analysis, we have predicted the arrangement of the phosphoric acids, formation of H-bonds in the system, and the contribution of different atoms toward H-bonding. We have also examined the stacking of 2-phenyl-1H,1'H-5,5'-bibenzo[d]imidazole molecules and how their arrangement changes with the increasing amount of PA in the system with the help of cluster analysis. From the molecular dynamics simulation conducted at different temperatures and phosphoric acid doping level, we have predicted the diffusion of phosphoric acid and monomer. As a dynamic quantity, we have also calculated ring flipping of the imidazole ring of the monomer.

Assembly of polyethyleneimine in the hexagonal mesophase of nonionic surfactant: effect of pH and temperature.

We investigate the dispersion of a pH responsive polymer, polyethyleneimine, PEI, in a hexagonal (H(1)) mesophase of a nonionic surfactant, C(12)E(9), and water, at pH ranging from basic (pH = 12.8) to acidic (pH = 1). While the C(12)E(9)/H(2)O phase behavior is independent of pH, we demonstrate that, in the PEI/C(12)E(9)/H(2)O system, changing the pH influences PEI-C(12)E(9) interactions, and thus, influences the isotropic-H(1) phase transition. With decrease in pH, there is increasing protonation of the PEI chain, and consequently, the chain extends. We show, using a combination of SAXs, optical microscopy and visual experiments, that the inclusion of PEI in a 1:1 surfactant-water mixture, lowers the hexagonal-isotropic transition temperature, T(HI). At higher pH = 12.8, T(HI) shows a pronounced decrease from 50 to 13 °C on addition of PEI, and the PEI/C(12)E(9)/H(2)O system forms a transparent gel. At pH = 1, we observe qualitatively different behavior and an opaque gel forms below T(HI) = 25 °C. The isotropic-H(1) transition, in turn, influences the phase separation of PEI chains from the C(12)E(9)/H(2)O system. 2D NMR ROESY data provides evidence that there are strong surfactant-PEI interactions at high pH that significantly reduce at lower pH. The NMR data is in accord with molecular dynamics simulations that show that surfactants strongly aggregate with unprotonated PEI chains, but not with fully protonated chains; thus, in this system, the pH controls a cascade of microstructural organization: increasing pH decreases chain protonation and increases polymer-surfactant interactions, resulting in suppression of the isotropic-H(1) transition to lower temperatures, thus, influencing the phase separation of PEI from the surfactant/water system.