Molecular Dynamics Simulation of Complex Reactivity with the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) Software Package.

Simulating chemically reactive phenomena such as proton transport on nanosecond to microsecond and beyond time scales is a challenging task. Ab initio methods are unable to currently access these time scales routinely, and traditional molecular dynamics methods feature fixed bonding arrangements that cannot account for changes in the system's bonding topology. The Multiscale Reactive Molecular Dynamics (MS-RMD) method, as implemented in the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) software package for the LAMMPS molecular dynamics code, offers a method to routinely sample longer time scale reactive simulation data with statistical precision. RAPTOR may also be interfaced with enhanced sampling methods to drive simulations toward the analysis of reactive rare events, and a number of collective variables (CVs) have been developed to facilitate this. Key advances to this methodology, including GPU acceleration efforts and novel CVs to model water wire formation are reviewed, along with recent applications of the method which demonstrate its versatility and robustness.

Self-assembly of nanocrystals into strongly electronically coupled all-inorganic supercrystals.

Colloidal nanocrystals of metals, semiconductors, and other functional materials can self-assemble into long-range ordered crystalline and quasicrystalline phases, but insulating organic surface ligands prevent the development of collective electronic states in ordered nanocrystal assemblies. We reversibly self-assembled colloidal nanocrystals of gold, platinum, nickel, lead sulfide, and lead selenide with conductive inorganic ligands into supercrystals exhibiting optical and electronic properties consistent with strong electronic coupling between the constituent nanocrystals. The phase behavior of charge-stabilized nanocrystals can be rationalized and navigated with phase diagrams computed for particles interacting through short-range attractive potentials. By finely tuning interparticle interactions, the assembly was directed either through one-step nucleation or nonclassical two-step nucleation pathways. In the latter case, the nucleation was preceded by the formation of two metastable colloidal fluids.

Probing the size-dependent polarizability of mesoscopic ionic clusters and their induced-dipole interactions.

Mesoscopic clusters composed of oppositely charged particles are ubiquitous in synthetic and biological soft materials. The effective interaction between these clusters is influenced by their polarizability, that is, the ability of their constituent charges to re-arrange in response to an external electrical field. Here, using coarse-grained simulations, we show that the polarizability of electrically neutral ionic clusters decreases as the number of constituent charges increases and/or their Coulombic interaction strength increases for various ion valencies, ion densities, and degrees of cluster boundary hardness. For clusters of random ionomers and their counterions, their polarizability is shown to depend on the number of polymer chains. The variation of the cluster polarizability with the cluster size indicates that throughout the assembly, the induced-dipole interactions between the clusters may be reduced substantially as they acquire more charges while maintaining zero net charge. Under certain conditions, the induced-dipole interactions may become repulsive, as inferred from our simulations with a polarizable solvent. As a result, the dipole-induced related interactions can serve as a counterbalancing force that contributes to the self-limiting aggregation of charge-containing assemblies.

Homopolymer self-assembly of poly(propylene sulfone) hydrogels via dynamic noncovalent sulfone-sulfone bonding.

Natural biomolecules such as peptides and DNA can dynamically self-organize into diverse hierarchical structures. Mimicry of this homopolymer self-assembly using synthetic systems has remained limited but would be advantageous for the design of adaptive bio/nanomaterials. Here, we report both experiments and simulations on the dynamic network self-assembly and subsequent collapse of the synthetic homopolymer poly(propylene sulfone). The assembly is directed by dynamic noncovalent sulfone-sulfone bonds that are susceptible to solvent polarity. The hydration history, specified by the stepwise increase in water ratio within lower polarity water-miscible solvents like dimethylsulfoxide, controls the homopolymer assembly into crystalline frameworks or uniform nanostructured hydrogels of spherical, vesicular, or cylindrical morphologies. These electrostatic hydrogels have a high affinity for a wide range of organic solutes, achieving >95% encapsulation efficiency for hydrophilic small molecules and biologics. This system validates sulfone-sulfone bonding for dynamic self-assembly, presenting a robust platform for controllable gelation, nanofabrication, and molecular encapsulation.

Surface polarization effects in confined polyelectrolyte solutions.

Understanding nanoscale interactions at the interface between two media with different dielectric constants is crucial for controlling many environmental and biological processes, and for improving the efficiency of energy storage devices. In this contributed paper, we show that polarization effects due to such dielectric mismatch remarkably influence the double-layer structure of a polyelectrolyte solution confined between two charged surfaces. Surprisingly, the electrostatic potential across the adsorbed polyelectrolyte double layer at the confining surface is found to decrease with increasing surface charge density, indicative of a negative differential capacitance. Furthermore, in the presence of polarization effects, the electrostatic energy stored in the double-layer structure is enhanced with an increase in the charge amplification, which is the absorption of ions on a like-charged surface. We also find that all of the important double-layer properties, such as charge amplification, energy storage, and differential capacitance, strongly depend on the polyelectrolyte backbone flexibility and the solvent quality. These interesting behaviors are attributed to the interplay between the conformational entropy of the confined polyelectrolytes, the Coulombic interaction between the charged species, and the repulsion from the surfaces with lower dielectric constant.

Multicanonical Monte Carlo ensemble growth algorithm.

We present an ensemble Monte Carlo growth method to sample the equilibrium thermodynamic properties of random chains. The method is based on the multicanonical technique of computing the density of states in the energy space. Such a quantity is temperature independent, and therefore microcanonical and canonical thermodynamic quantities, including the free energy, entropy, and thermal averages, can be obtained by reweighting with a Boltzmann factor. The algorithm we present combines two approaches: The first is the Monte Carlo ensemble growth method, where a "population" of samples in the state space is considered, as opposed to traditional sampling by long random walks, or iterative single-chain growth. The second is the flat-histogram Monte Carlo, similar to the popular Wang-Landau sampling, or to multicanonical chain-growth sampling. We discuss the performance and relative simplicity of the proposed algorithm, and we apply it to known test cases.

Control of Ionic Mobility via Charge Size Asymmetry in Random Ionomers.

Solid polymer electrolytes are considered a promising alternative to traditional liquid electrolytes in energy storage applications because of their good mechanical properties, and excellent thermal and chemical stability. A gap, however, still exists in understanding ion transport mechanisms and improving ion transport in solid polymer electrolytes. Therefore, it is crucial to bridge composition-structure and structure-property relationships. Here, we demonstrate that size asymmetry, λ, represented by the ratio of counterion to charged monomer size, plays a key role both in the nanostructure and in the ionic dynamics. More specifically, when the nanostructure is modified by an external electric field such that the mobility cannot be described by linear response theory, two situations arise. The ionic mobility increases as λ decreases (small counterions) in the weak electrostatics (high dielectric constant) regime, whereas in systems with strong electrostatic interactions, ionomers with higher size symmetry (λ ≈ 1) display higher ionic mobility. Moreover, ion transport is found to be dominated by the hopping of the ions and not by moving ionic clusters (also known as "vehicular" charge transport). These results serve as a guide for designing ion-containing polymers for ion transport related applications.

Water follows polar and nonpolar protein surface domains.

The conformation of water around proteins is of paramount importance, as it determines protein interactions. Although the average water properties around the surface of proteins have been provided experimentally and computationally, protein surfaces are highly heterogeneous. Therefore, it is crucial to determine the correlations of water to the local distributions of polar and nonpolar protein surface domains to understand functions such as aggregation, mutations, and delivery. By using atomistic simulations, we investigate the orientation and dynamics of water molecules next to 4 types of protein surface domains: negatively charged, positively charged, and charge-neutral polar and nonpolar amino acids. The negatively charged amino acids orient around 98% of the neighboring water dipoles toward the protein surface, and such correlation persists up to around 16 Å from the protein surface. The positively charged amino acids orient around 94% of the nearest water dipoles against the protein surface, and the correlation persists up to around 12 Å. The charge-neutral polar and nonpolar amino acids are also orienting the water neighbors in a quantitatively weaker manner. A similar trend was observed in the residence time of the nearest water neighbors. These findings hold true for 3 technically important enzymes (PETase, cytochrome P450, and organophosphorus hydrolase). Our results demonstrate that the water-amino acid degree of correlation follows the same trend as the amino acid contribution in proteins solubility, namely, the negatively charged amino acids are the most beneficial for protein solubility, then the positively charged amino acids, and finally the charge-neutral amino acids.

Manipulation of Confined Polyelectrolyte Conformations through Dielectric Mismatch.

We demonstrate that a highly charged polyelectrolyte confined in a spherical cavity undergoes reversible transformations between amorphous conformations and a four-fold symmetry morphology as a function of dielectric mismatch between the media inside and outside the cavity. Surface polarization due to dielectric mismatch exhibits an extra "confinement" effect, which is most pronounced within a certain range of the cavity radius and the electrostatic strength between the monomers and counterions and multivalent counterions. For cavities with a charged surface, surface polarization leads to an increased amount of counterions adsorbed in the outer side, further compressing the confined polyelectrolyte into a four-fold symmetry morphology. The equilibrium conformation of the chain is dependent upon several key factors including the relative permittivities of the media inside and outside the cavity, multivalent counterion concentration, cavity radius relative to the chain length, and interface charge density. Our findings offer insights into the effects of dielectric mismatch in packaging and delivery of polyelectrolytes across media with different relative permittivities. Moreover, the reversible transformation of the polyelectrolyte conformations in response to environmental permittivity allows for potential applications in biosensing and medical monitoring.

Efficient encapsulation of proteins with random copolymers.

Membraneless organelles are aggregates of disordered proteins that form spontaneously to promote specific cellular functions in vivo. The possibility of synthesizing membraneless organelles out of cells will therefore enable fabrication of protein-based materials with functions inherent to biological matter. Since random copolymers contain various compositions and sequences of solvophobic and solvophilic groups, they are expected to function in nonbiological media similarly to a set of disordered proteins in membraneless organelles. Interestingly, the internal environment of these organelles has been noted to behave more like an organic solvent than like water. Therefore, an adsorbed layer of random copolymers that mimics the function of disordered proteins could, in principle, protect and enhance the proteins' enzymatic activity even in organic solvents, which are ideal when the products and/or the reactants have limited solubility in aqueous media. Here, we demonstrate via multiscale simulations that random copolymers efficiently incorporate proteins into different solvents with the potential to optimize their enzymatic activity. We investigate the key factors that govern the ability of random copolymers to encapsulate proteins, including the adsorption energy, copolymer average composition, and solvent selectivity. The adsorbed polymer chains have remarkably similar sequences, indicating that the proteins are able to select certain sequences that best reduce their exposure to the solvent. We also find that the protein surface coverage decreases when the fluctuation in the average distance between the protein adsorption sites increases. The results herein set the stage for computational design of random copolymers for stabilizing and delivering proteins across multiple media.

Ionic Correlations in Random Ionomers.

Understanding the electrostatic interactions in ion-containing polymers is crucial to better design shape memory polymers and ion-conducting membranes for multiple energy storage and conversion applications. In molten polymers, the dielectric permittivity is low, generating strong ionic correlations that lead to clustering of the charges. Here, we investigate the influence of electrostatic interactions on the nanostructure of randomly charged polymers (ionomers) using coarse-grained molecular dynamics simulations. Densely packed branched structures rich in charged species are found as the strength of the electrostatic interactions increases. Polydispersity in charge fraction and composition combined with ion correlations leads to percolated nanostructures with long-range fluctuations. We identify the percolation point at which the ionic branched nanostructures percolate and offer a rigorous investigation of the statistics of the shape of the aggregates. The extra degree of freedom introduced by the charge polydispersity leads to bicontinuous structures with a broad range of compositions, similar to neutral A-B random copolymers, as well as to desirable percolated ionic structure in randomly charged-neutral diblock copolymers. These findings provide insight into the design of conducting and robust nanostructures in ion-containing polymers.

Random heteropolymers preserve protein function in foreign environments.

The successful incorporation of active proteins into synthetic polymers could lead to a new class of materials with functions found only in living systems. However, proteins rarely function under the conditions suitable for polymer processing. On the basis of an analysis of trends in protein sequences and characteristic chemical patterns on protein surfaces, we designed four-monomer random heteropolymers to mimic intrinsically disordered proteins for protein solubilization and stabilization in non-native environments. The heteropolymers, with optimized composition and statistical monomer distribution, enable cell-free synthesis of membrane proteins with proper protein folding for transport and enzyme-containing plastics for toxin bioremediation. Controlling the statistical monomer distribution in a heteropolymer, rather than the specific monomer sequence, affords a new strategy to interface with biological systems for protein-based biomaterials.

Orbitals for classical arbitrary anisotropic colloidal potentials.

Coarse-grained potentials are ubiquitous in mesoscale simulations. While various methods to compute effective interactions for spherically symmetric particles exist, anisotropic interactions are seldom used, due to their complexity. Here we describe a general formulation, based on a spatial decomposition of the density fields around the particles, akin to atomic orbitals. We show that anisotropic potentials can be efficiently computed in numerical simulations using Fourier-based methods. We validate the field formulation and characterize its computational efficiency with a system of colloids that have Gaussian surface charge distributions. We also investigate the phase behavior of charged Janus colloids immersed in screened media, with screening lengths comparable to the colloid size. The system shows rich behaviors, exhibiting vapor, liquid, gel, and crystalline morphologies, depending on temperature and screening length. The crystalline phase only appears for symmetric Janus particles. For very short screening lengths, the system undergoes a direct transition from a vapor to a crystal on cooling; while, for longer screening lengths, a vapor-liquid-crystal transition is observed. The proposed formulation can be extended to model force fields that are time or orientation dependent, such as those in systems of polymer-grafted particles and magnetic colloids.

The Effect of Maternal Pertussis Immunization on Infant Vaccine Responses to a Booster Pertussis-Containing Vaccine in Vietnam.

BACKGROUND: Maternal vaccination with an acellular pertussis (aP)-containing vaccine is a recommended strategy in a growing number of industrialized countries, to protect young infants from disease. Little is known on the effect of this strategy in low- and middle-income countries. Following a previous report on the effect of adding a pertussis and diphtheria component to the tetanus vaccination program in pregnant women in Vietnam, we report on infant immune responses to a booster aP vaccine dose in this randomized controlled clinical trial. METHODS: Thirty infants of Tdap (tetanus, diphtheria, and acellular pertussis)-vaccinated pregnant women and 37 infants of women vaccinated with a tetanus-only vaccine received a fourth aP-containing vaccine dose in the second year of life. Blood was taken 1 month after the fourth infant dose. Immunoglobulin G (IgG) antibodies against pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (Prn), tetanus toxoid (TT), and diphtheria toxoid (DT) were measured using commercially available enzyme-linked immunosorbent assays (ELISA). RESULTS: One month after the booster dose, significantly lower antibody titers were measured in the Tdap group for anti-TT IgG (P < .001) only. Anti-DT IgG, anti-PT IgG, anti-Prn IgG, and anti-FHA IgG antibody titers were comparable for both groups. A rise in antibody concentrations was elicited for all (except DT) antigens after boosting. CONCLUSIONS: The present results indicate that the blunting of infant pertussis responses induced by maternal immunization, measured after a primary series of aP vaccines, was resolved with the booster aP vaccine dose. These results add to the evidence for national and international decision makers on maternal immunization as a vaccination strategy for protection of young infants against infectious diseases.

Pertussis vaccination during pregnancy in Vietnam: Results of a randomized controlled trial Pertussis vaccination during pregnancy.

A pertussis vaccination during pregnancy has recently been adopted in several countries to indirectly protect young infants. This study assessed the effect of adding a pertussis component to the tetanus vaccination, in the pregnancy immunization program in Vietnam. A randomized controlled trial was performed. Pregnant women received either a Tdap (tetanus, diphtheria acellular pertussis) vaccine or a tetanus only vaccine between 19 and 35 weeks' gestational age. Immunoglobulin G (IgG) against tetanus (TT), diphtheria (DT), pertussis toxin (PT), filamentous hemaglutinin (FHA) and pertactin (Prn) were measured using commercial ELISA tests, at baseline, 1 month after maternal vaccination, at delivery, and in infants from cord blood and before and after the primary series (EPI: month 2-3-4) of a pertussis containing vaccine. Significantly higher geometric mean concentrations (GMC) were observed for all 3 measured pertussis antigens in the offspring of the Tdap group, up to 2 months of age. One month after completion of the primary infant vaccination schedule, anti-Prn GMC, but not anti-PT and anti-FHA GMCs, was significantly (p=0.006) higher in the control group. Maternal antibodies induced by vaccination during pregnancy close the susceptibility gap for pertussis in young infants. Limited interference with the infant vaccine responses was observed. Whether this interference effect disappears with the administration of a fourth vaccine dose is further studied.

Generic, phenomenological, on-the-fly renormalized repulsion model for self-limited organization of terminal supraparticle assemblies.

Self-limited, or terminal, supraparticles have long received great interest because of their abundance in biological systems (DNA bundles and virus capsids) and their potential use in a host of applications ranging from photonics and catalysis to encapsulation for drug delivery. Moreover, soft, uniform colloidal aggregates are a promising candidate for quasicrystal and other hierarchical assemblies. In this work, we present a generic coarse-grained model that captures the formation of self-limited assemblies observed in various soft-matter systems including nanoparticles, colloids, and polyelectrolytes. Using molecular dynamics simulations, we demonstrate that the assembly process is self-limited when the repulsion between the particles is renormalized to balance their attraction during aggregation. The uniform finite-sized aggregates are further shown to be thermodynamically stable and tunable with a single dimensionless parameter. We find large aggregates self-organize internally into a core-shell morphology and exhibit anomalous uniformity when the constituent nanoparticles have a polydisperse size distribution.

Coverage of the expanded program on immunization in Vietnam: Results from 2 cluster surveys and routine reports.

UNLABELLED: The Expanded Program on Immunization (EPI) in Vietnam began in 1981 and reached a 87% national coverage rate in 1987. To investigate the vaccination coverage and trends in time of the EPI in Vietnam, 2 vaccine coverage cluster surveys have been conducted in 2003 and 2009. Information on EPI-vaccine coverage in children (aged 0-23 months - 7 y of age), in women of childbearing age and in pregnant women, was collected through '30 cluster surveys' in 2003 and 2009 (according to the World Health Organization (WHO) methodology) and through routine annual EPI coverage reports for the period 2001-2008. By comparing both cluster survey studies with each other, as well as with routinely collected data, we aim to improve future evaluation of the vaccination coverage in Vietnam and deduce recommendations for the immunization program. According to both methods, the national targets were reached for most of the vaccines: over 90% of children are fully immunized by 1 y of age, 80% Tetanus Toxoid 2 Plus (TT2+) coverage is reached for pregnant women, and 90% TT2+ for childbearing aged women. The cluster surveys identified higher coverage rates compared to the routinely reported data in some provinces regarding the percentage of fully immunized children by the age of 1 year, and confirmed a low coverage rate for hepatitis B birth dose vaccination in all surveyed sites. CONCLUSION: Both methods of coverage assessment suggest that national targets are reached, for most but not all vaccines and not in all regions. Managing stock pile issues, addressing safety issues and tailoring policy for remote areas, are important elements to maintain and further improve these coverage figures.

Terminal supraparticle assemblies from similarly charged protein molecules and nanoparticles.

Self-assembly of proteins and inorganic nanoparticles into terminal assemblies makes possible a large family of uniformly sized hybrid colloids. These particles can be compared in terms of utility, versatility and multifunctionality to other known types of terminal assemblies. They are simple to make and offer theoretical tools for designing their structure and function. To demonstrate such assemblies, we combine cadmium telluride nanoparticles with cytochrome C protein and observe spontaneous formation of spherical supraparticles with a narrow size distribution. Such self-limiting behaviour originates from the competition between electrostatic repulsion and non-covalent attractive interactions. Experimental variation of supraparticle diameters for several assembly conditions matches predictions obtained in simulations. Similar to micelles, supraparticles can incorporate other biological components as exemplified by incorporation of nitrate reductase. Tight packing of nanoscale components enables effective charge and exciton transport in supraparticles and bionic combination of properties as demonstrated by enzymatic nitrate reduction initiated by light absorption in the nanoparticle.

Self-assembly of reconfigurable colloidal molecules.

The lock-and-key colloidal particles of Sacanna et al. are novel "dynamic" building blocks consisting of a central spherical colloidal particle (key) attached to a finite number of dimpled colloidal particles (locks) via depletion interactions strong enough to bind the particles together but weak enough that the locks are free to rotate around the key. This rotation imbues a mechanical reconfigurability to these colloidal "molecules". Here we use molecular simulation to predict that these lock-and-key building blocks can self-assemble into a wide array of complex crystalline structures that are tunable via a set of reconfigurability dimensions: the number of locks per building block, bond length, size ratio, confinement, and lock mobility. We demonstrate that, with reconfigurability, ordered structures - such as random triangle square tilings - assemble, despite being kinetically inaccessible with non-reconfigurable but similar building blocks.

Coexistence of spinodal instability and thermal nucleation in thin-film rupture: insights from molecular levels.

Despite extensive investigation using hydrodynamic models and experiments over the past decades, there remain open questions regarding the origin of the initial rupture of thin liquid films. One of the reasons that makes it difficult to identify the rupture origin is the coexistence of two dewetting mechanisms, namely, thermal nucleation and spinodal instability, as observed in many experimental studies. Using a coarse-grained model and large-scale molecular dynamics simulations, we are able to characterize the very early stage of dewetting in nanometer-thick liquid-metal films wetting a solid substrate. We observe the features characteristic of both spinodal instability and thermal nucleation in the spontaneously dewetting films and show that these two macroscopic mechanisms share a common origin at molecular levels.