The structure of a network polymer determines its properties and behavior. And the formation of network topology depends on the chemistry and process during the polymerization. In this study, we described an in silico polymerization approach based on molecular dynamics simulation. The approach also incorporated the description of network topology using graph theory to monitor and even control the network formation. As a study case, the chain growth polymerization of poly(ethylene glycol) (PEG) nanogels is simulated and the impact of the reaction time and concentration of reactants on the topological features of the nanogels are analyzed. When the monomer concentration increases, the percentage of defects, including dangling chains, primary loops and excessive chains in secondary loops, decreases. Moreover, the reactant concentration also has a strong influence on the resulting network topology, leading to a higher percentage of smaller cycles.

We explored the potential for membrane materials to reduce energy and carbon requirements for the separation of aliphatic hydrocarbon feedstocks and products. We developed a series of fluorine-rich poly(arylene amine) polymer membranes that feature rigid polymer backbones with segregated perfluoroalkyl side chains. This combination imbues the polymers with resistance to dilation induced by hydrocarbon immersion without the loss of solution-based membrane fabrication techniques. These materials exhibit good separation of liquid-phase alkane isomers at ambient temperatures. The integration of these polymeric membranes into fuel and chemical feedstock separation processes was investigated in a series of experiments. Technoeconomic analyses based on these experiments indicate that the best-performing membrane materials can substantially reduce the energy costs and associated carbon emissions of hydrocarbon separations (two to 10 times, depending on product specifications).

Anion exchange membranes offer a promising alternative to the more expensive proton exchange membrane fuel cells; however, hydroxide ion conductivity in anion exchange membranes is poorly understood. In this paper, we use classical molecular dynamics simulations to study the structure and ion transport properties of four different polyethylene-based membranes prepared from ethylene-co-vinyl-acetate (EVA). We examine the microstructure of the membranes and find that polymers with a narrow cavity size distribution have tighter packing of water molecules around hydroxide ions, compared to membranes with a broad cavity distribution. We calculate the structure factor of the hydrated membranes and find a peak between 1 and 4 nm(-1), characteristic of ionic clusters in these materials. We estimate the self-diffusion coefficient of water and hydroxide ions and find that water molecules have a higher diffusion than hydroxide ions across all systems. The trends in hydroxide diffusion align well with experimental conductivity measurements. For systems with broad cavities, water facilitates hydroxide diffusion through vehicular transport, and in systems with narrow cavities, both ion hopping and vehicular transport are observed; this is quantified by calculating ion-ion and ion-solvent correlations through the Onsager transport coefficient framework.

Anion exchange membranes are used in alkaline fuel cells and offer a promising alternative to the more expensive proton exchange membrane fuel cells. However, hydroxide ion conductivity in anion exchange membranes is low, and the quest for membranes with superior ion conductivity, mechanical robustness, and chemical stability is ongoing. In this study, we use classical molecular dynamics simulations to study hydroxide ion transport and mechanical properties of eight different hydrated polyolefin-based membranes, to provide a molecular-level understanding of the structure-function relationships in these systems. We examine the microstructure of the membranes and find that polymers with narrow cavity size distribution have tighter packing of water molecules around hydroxide ions. We estimate the self-diffusion coefficient of water and hydroxide ions and find that water molecules have a higher diffusion than hydroxide ions across all systems. The trends in hydroxide diffusion align well with experimental conductivity measurements. Water facilitates hydroxide diffusion, and this is clearly observed when the hydration level is varied for the same polymer chemistry. In systems with narrow cavities and tightly bound hydroxide ions, hydroxide diffusion is the lowest, underscoring the fact that water channels facilitate hydroxide transport. Finally, we apply uniaxial deformation to calculate the mechanical properties of these systems and find that polymers with higher hydration levels show poor mechanical properties. Atomistic molecular dynamics models can accurately capture the trade-off between hydroxide transport and mechanical performance in anion exchange membranes and allow us to screen new candidates more efficiently.

Macromolecules such as proteins conjugated to polyethylene glycol (PEG) have been employed in therapeutic drug applications, and recent research has emphasized the potential of varying polymer architectures and conjugation strategies to achieve improved efficacy. In this study, we performed atomistic molecular dynamics simulations of bovine serum albumin (BSA) conjugated to 5 kDa PEG polymers in an array of schemes, including varied numbers of attached chains, grafting density, and nonlinear architectures. Nonlinear architectures included U-shaped PEG, Y-shaped PEG, and poly(oligoethylene glycol methacrylate) (POEGMA). Buried surface area calculations and polymer volume map analyses revealed that volume exclusion behaviors of the high grafting density conjugate promoted additional protein-polymer interactions when compared to simply increasing numbers of conjugated chains uniformly across the protein surface. Investigation of nonlinear polymer architectures showed that stable polymer-lysine loop-like conformations seen in previous conjugate designs were more variable in prevalence, especially in POEGMA, which contained short oligomer PEG chains. The findings of this comprehensive study of alternate PEGylation schemes of BSA provide critical insight into molecular patterns of interaction within bioconjugates and highlight their importance in the future of controlled modification of conjugate system parameters.

Covalently bonded proteins and synthetic polymers allow for the design of materials of interest for practical biological and non-biological applications. Chemical functionality, specificity, selectivity, and stimuli response can be engineered through a fundamental understanding of protein-polymer interactions. An overview of the significant role that computer simulations, at the atomistic and mesoscale levels, have played in our understanding of protein-polymer conjugates is provided in this review. Challenges for further development of molecular simulation techniques are discussed, as well as the need for a close interrelation with systematic experimental studies.

Therapeutic proteins have increasingly been used in modern medical applications, but their effectiveness is limited by factors such as stability and blood circulation time. Recently, there has been significant research into covalently linking polyethylene glycol polymer chains (PEG) to proteins, known as PEGylation, to mitigate these issues. In this work, an atomistic molecular dynamics study of N-terminal conjugated PEG-BSA (bovine serum albumin) was conducted with varying PEG molecular weights (2, 5, 10, and 20 I(Da) to probe PEG-BSA interactions and evaluate the effect of polymer length on dynamics. It was found that the affinity of PEG toward the protein surface increased as a function of PEG molecular weight and that a certain weight (around 10 kDa) was required to promote protein-polymer interactions. Additionally, preferential interactions were monitored through formed contacts and hotspots were identified. PEG chains coordinating in looplike conformations were found near lysine residues. Also, it was found that hydrophobic interactions played an important role in promoting PEG-BSA interactions as the PEG molecular weight increased. The results provide insight into underlying mechanisms behind transitions in PEG conformations and will aid in future design of effective PEGylated drug molecules.

Poly(ethylene glycol) (PEG)-based nanogels are attractive for biomedical applications due to their biocompatibility, versatile end group chemistry, and ability to sterically shield encapsulated drug molecules. The characteristics of a hydrogel network govern the encapsulation and efficient delivery of drug molecules for a target application. A molecular-level description of network topology can complement experimental investigations to understand its effects on the structural properties of these nanogels. In this work, atomistic molecular simulations of heterogeneous, nonideal PEG-diacrylate (PEGDA) nanogels are presented. The effects of cross-linking density and topological features on the structural properties of PEGDA nanogels were studied. The average functionality was controlled to systematically study the effect of cross-linking density on the radius of gyration, shape, and mesh size of the nanogels. For a given average functionality, the impact of distinct network topologies on the structural properties was also studied. The aspect ratios, based on the gyration tensor, were calculated to characterize the shapes of these nanogels for different topologies. Nanogel structures with higher cross-linking densities showed a globular shape, while structures with lower cross-linking density showed shape anisotropy. The distribution and connectivity of the cross-linked junctions played a key role in determining the size and shape anisotropy of PEGDA nanogels; the number of unreacted chain ends and their connectivity directly affected the anisotropy. The mesh size, denoted by the limiting "free volume element" present in the nanogel samples, does not show a significant change with increasing average functionality. This work provides insight into the structural properties of heterogeneous hydrogels that aid the design of nonideal nanogel networks for a targeted drug delivery application.

The conjugation of polyethylene glycol (PEG) to proteins, known as PEGylation, has increasingly been employed to expand the efficacy of therapeutic drugs. Recently, research has emphasized the effect of the conjugation site on protein-polymer interactions. In this study, we performed atomistic molecular dynamics (MD) simulations of lysine 116 PEGylated bovine serum albumin (BSA) to illustrate how conjugation near a hydrophobic pocket affects the conjugate's dynamics and observed altered low mode vibrations in the protein. MD simulations were performed for a total of 1.5 μs for each PEG chain molecular mass from 2 to 20 kDa. Analysis of preferential PEG-BSA interactions showed that polymer behavior was also affected as proximity to the attractive protein surface patches promoted interactions in small (2 kDa) PEG chains, while the confined environment of the conjugation site reduced the expected BSA surface coverage when the polymer molecular mass increased to 10 kDa. This thorough analysis of PEG-BSA interactions and polymer dynamics increases the molecular understanding of site-specific PEGylation and enhances the use of protein-polymer conjugates as therapeutics.

Almost all commercial proteins are purified using ammonium sulfate precipitation. Protein-polymer conjugates are synthesized from pure starting materials, and the struggle to separate conjugates from polymer, native protein, and from isomers has vexed scientists for decades. We have discovered that covalent polymer attachment has a transformational effect on protein solubility in salt solutions. Here, protein-polymer conjugates with a variety of polymers, grafting densities, and polymer lengths are generated using atom transfer radical polymerization. Charged polymers increase conjugate solubility in ammonium sulfate and completely prevent precipitation even at 100% saturation. Atomistic molecular dynamic simulations show the impact is driven by an anti-polyelectrolyte effect from zwitterionic polymers. Uncharged polymers exhibit polymer length-dependent decreased solubility. The differences in salting-out are then used to simply purify mixtures of conjugates and native proteins into single species. Increasing protein solubility in salt solutions through polymer conjugation could lead to many new applications of protein-polymer conjugates.

The field of protein-polymer conjugates has suffered from a lack of predictive tools and design guidelines to synthesize highly active and stable conjugates. In order to develop this type of information, structure-function-dynamics relationships must be understood. These relationships depend strongly on protein-polymer interactions and how these influence protein dynamics and conformations. Probing nanoscale interactions is experimentally difficult, but computational tools, such as molecular dynamics simulations, can easily obtain atomic resolution. Atomistic molecular dynamics simulations were used to study α-chymotrypsin (CT) densely conjugated with either zwitterionic, positively charged, or negatively charged polymers. Charged polymers interacted with the protein surface to varying degrees and in different regions of the polymer, depending on their flexibilities. Specific interactions of the negatively charged polymer with CT caused structural deformations in CT's substrate binding pocket and active site while no deformations were observed for zwitterionic and positively charged polymers. Attachment of polymers displaced water molecules from CT's surface into the polymer phase and polymer hydration correlated with the Hofmeister series.

The power and elegance of protein-polymer conjugates has solved many vexing problems for society. Rational design of these complex covalent hybrids depends on a deep understanding of how polymer physicochemical properties impact the conjugate structure-function-dynamic relationships. We have generated a large family of chymotrypsin-polymer conjugates which differ in polymer length and charge, using grafting-from atom-transfer radical polymerization, to elucidate how the polymers influenced enzyme structure and function at pHs that would unfold and inactivate the enzyme. We also used molecular dynamics simulations to deepen our understanding of protein-polymer intramolecular interactions. Remarkably, the data revealed that, contrary to current thoughts on how polymers stabilize proteins, appropriately designed polymers actually stabilize partially unfolded intermediates and assist in refolding to an active conformation. Long, hydrophilic polymers minimized interfacial interactions in partially unfolded conjugates leading to increased stabilization. The design of covalently attached intramolecular biomimetic chaperones that drive protein refolding could have far reaching consequences.

Increasing demand for hybrid materials that merge the synthetic and biological areas in drug industries requires in-depth knowledge of the individual components and their contributions to these complexes. Coarse-grained (CG) models developed for proteins and polymers exist, yet there is a lack of understanding of the cross interactions when these two groups of materials integrate to build a complex. In this work, we characterized the nonbonded interactions between poly(ethylene glycol) (PEG) and amino acids in a Martini CG model utilizing state-of-the-art quantum mechanics calculations of interaction energies. The parameter set proposed, was validated by assessing the polymer density in the vicinity of individual amino acids obtained from available all-atomistic molecular dynamic simulations of plasma proteins. Our results revealed the necessity of protein-polymer interaction parameterization at the CG level to avoid overestimation of polymer association when employing other PEG models within the Martini framework.

Recent studies have revealed the importance and the active contribution of the RANKL/OPG/RANK pathway in many bone diseases including different forms of common osteoporosis. In this study, we present an extensive atomistic molecular dynamic study of the OPG/RANKL system. Within the molecular models, we varied the number of OPG molecules bound to the RANKL trimer and carried out a study to determine how the binding affinity of the OPG/RANKL system changes as a function of OPG concentration. The molecular mechanics Poisson-Boltzmann surface area method was used to analyze binding free energies. It is shown that the binding affinity decreases with increasing numbers of OPG molecules. Additionally, conformational changes of RANKL, interactions between the N-terminus outlier module of OPG with RANKL, and residues that play an important role in the binding of OPG to RANKL trimer were investigated. A probable cause for unfavorable binding for a third OPG molecule was found. Along with the currently available experimental studies, this computational study will be valuable for the comprehensive understanding of OPG/ RANKL at the atomistic level.