Free Monomers Research Articles

Stimuli-responsive nanoparticles from RAFT dispersion polymerization-induced self-assembly (PISA) of N-phenylacrylamide copolymerized with a boronic acid-substituted derivative

Boronic acid (BA) moieties confer a variety of stimuli-response properties upon polymers. PISA is the most efficient technique for the preparation of core–shell nanoparticles (NPs), however aqueous dispersion PISA of free BA-containing monomers is complicated by the formation of the boroxine anhydride at the hydrophobic core. In the present work, dispersion reversible addition-fragmentation chain transfer (RAFT) copolymerization of a free BA-containing derivative of N-phenylacrylamide yields NP morphologies which are different to those formed from the equivalent PISA homopolymerization without BA. Depending on conditions, PISA results in spheres, rods, and worms with colloidal stability improved by using a higher fraction of the non-stimuli responsive monomer to give large compound micelles. Post-polymerization stimuli-response from the resultant PISA dispersion through hydrolysis of boroxine-rich copolymer NPs by dilution with the aqueous dispersion solvent or with water yields micron-sized worms, lamellae, and vesicles. Self-assembly to higher order morphologies is driven by the extent of hydrolysis. The resultant free BA-containing NPs becoming smaller and spherical upon basification and glucose addition.

Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a 'snap-through' instability.

Mitochondrial fission is controlled by dynamin proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membrane to achieve fission, but details are not well understood. However, dynamins can also remodel membranes by inducing negative Gaussian curvature, the type of curvature required for completion of fission. Here, we examine how these drastically different mechanisms synergistically exert their influences on a membrane, via a mechanical model calibrated with small-angle X-ray scattering structural data. We find that free dynamin can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of dynamin assembly, and paradoxically disassembly, can lead to diverse pathways to scission.

Adaptive Reaktion bei der Lösung von flexiblen Molekülen: Oligohydrate von 4‐Hydroxy‐2‐butanon

AbstractDurch Wasser hervorgerufene Strukturveränderungen spielen eine zentrale Rolle in der Chemie und Biologie, sind aber auf molekularer Ebene nach wie vor schwer vorherzusagen, zu messen und zu kontrollieren. Hier untersuchen wir in der Gasphase die größenabhängige Wasseraggregation am flexiblen Molekül 4‐Hydroxy‐2‐butanon und modellieren die Konformationsanpassungsfähigkeit flexibler Substrate an Wirtswassergerüste, sowie die Präferenzen für sequentielles Tröpfchenwachstum. Das Experiment wurde mittels breitbandiger Rotationsspektroskopie durchgeführt und mit quantenchemischen Berechnungen nachvollzogen. Experimentell wurden vom Di‐ bis zum Pentahydrat (4‐Hydroxy‐2‐butanon‐(H2O)n=2–5) zwei verschiedene Isomere beobachtet, einschließlich der 18O‐Isotopologen für die Di‐ und Trihydrate. Um Wassermoleküle effektiv unterzubringen, verändert sich interessanterweise das schwere Atomgerüst von 4‐Hydroxy‐2‐butanon in jedem beobachteten Isomer und entspricht nicht der stabilen Konformation des freien Monomers. Alle Solvate gehen von der Alkoholgruppe (Protonendonor) aus, behalten aber die Carbonylgruppe als sekundären Bindungspunkt bei. Die Wassergerüste ähneln stark denen in reinen Wasserclustern und balancieren zwischen der Fähigkeit von 4‐Hydroxy‐2‐butanon, die Orientierung und Position der Wassermoleküle zu steuern, und der Fähigkeit von Wasser, die Konformation des Monomers zu modulieren. Die vorliegende Arbeit liefert somit eine genaue molekulare Beschreibung, wie sich torsionsflexible Moleküle im Verlauf der fortschreitenden Solvatation dynamisch an Wasser anpassen.

Adaptive Response to Solvation in Flexible Molecules: Oligo Hydrates of 4-Hydroxy-2-butanone.

Structural changes induced by water play a pivotal role in chemistry and biology but remain challenging to predict, measure, and control at molecular level. Here we explore size-governed gas-phase water aggregation in the flexible molecule 4-hydroxy-2-butanone, modeling the conformational adaptability of flexible substrates to host water scaffolds and the preference for sequential droplet growth. The experiment was conducted using broadband rotational spectroscopy, rationalized with quantum chemical calculations. Two different isomers were observed experimentally from the di- to the pentahydrates (4-hydroxy-2-butanone-(H2O)n=2-5), including the 18O isotopologues for the di- and trihydrates. Interestingly, to accommodate water molecules effectively, the heavy atom skeleton of 4-hydroxy-2-butanone reshapes in every observed isomer and does not correspond to the stable conformer of the free monomer. All solvates initiate from the alcohol group (proton donor) but retain the carbonyl group as secondary binding point. The water scaffolds closely resemble those found in the pure water clusters, balancing between the capability of 4-hydroxy-2-butanone for steering the orientation and position of the water molecules and the ability of water to modulate the monomer's conformation. The present work thus provides an accurate molecular description on how torsionally flexible molecules dynamically adapt to water along progressing solvation.

New reducing agents and optimized redox techniques: Formaldehyde-free for the sustainable production of emulsion polymers

In April 2024, Brueggemann announced that at the American Coatings Show (30 April to 2 May 2024 in Indianapolis, booth 1060), Brüggemann would showcase their advancements in environmentally friendly reducing agents and processes for the production of emulsion polymers used in coatings, inks and adhesives. The company is highlighting its formaldehyde-free, multi-constituent sulfur-based Bruggolite® products, which are suitable for use under a wide variety of conditions. These products are claimed to also offer increased reactivity for higher performance at lower dosages and they can reportedly be used to achieve low to non-detectable levels of free monomer. They are claimed to be compliant with strict regulatory requirements throughout the world and most reportedly have FDA clearance for direct food contact. Formaldehyde-free for a wide range of applications

Thermodynamics of oligomerization and Helix-to-sheet structural transition of amyloid β-protein on anionic phospholipid vesicles

Understanding oligomerization and aggregation of the amyloid-β protein is important to elucidate the pathological mechanisms of Alzheimer's disease, and lipid membranes play critical roles in this process. In addition to studies reported by other groups, our group has also reported that the negatively-charged lipid bilayers with a high positive curvature induced α-helix-to-β-sheet conformational transitions of amyloid-β-(1–40) upon increase in protein density on the membrane surface and promoted amyloid fibril formation of the protein. Herein, we investigated detailed mechanisms of the conformational transition and oligomer formation of the amyloid-β protein on the membrane surface. Changes in the fractions of the three protein conformers (free monomer, membrane-bound α-helix-rich conformation, and β-sheet-rich conformation) were determined from the fluorescent spectral changes of the tryptophan probe in the protein. The helix-to-sheet structural transition on the surface was described by a thermodynamic model of octamer formation driven by entropic forces including hydrophobic interactions. These findings provide useful information for understanding the self-assembly of amyloidogenic proteins on lipid membrane surfaces.

Native Mass Spectrometry Dissects the Structural Dynamics of an Allosteric Heterodimer of SARS-CoV-2 Nonstructural Proteins.

Structure-based drug design, which relies on precise understanding of the target protein and its interaction with the drug candidate, is dramatically expedited by advances in computational methods for candidate prediction. Yet, the accuracy needs to be improved with more structural data from high throughput experiments, which are challenging to generate, especially for dynamic and weak associations. Herein, we applied native mass spectrometry (native MS) to rapidly characterize ligand binding of an allosteric heterodimeric complex of SARS-CoV-2 nonstructural proteins (nsp) nsp10 and nsp16 (nsp10/16), a complex essential for virus survival in the host and thus a desirable drug target. Native MS showed that the dimer is in equilibrium with monomeric states in solution. Consistent with the literature, well characterized small cosubstrate, RNA substrate, and product bind with high specificity and affinity to the dimer but not the free monomers. Unsuccessfully designed ligands bind indiscriminately to all forms. Using neutral gas collision, the nsp16 monomer with bound cosubstrate can be released from the holo dimer complex, confirming the binding to nsp16 as revealed by the crystal structure. However, we observed an unusual migration of the endogenous zinc ions bound to nsp10 to nsp16 after collisional dissociation. The metal migration can be suppressed by using surface collision with reduced precursor charge states, which presumably resulted in minimal gas-phase structural rearrangement and highlighted the importance of complementary techniques. With minimal sample input (∼μg), native MS can rapidly detect ligand binding affinities and locations in dynamic multisubunit protein complexes, demonstrating the potential of an "all-in-one" native MS assay for rapid structural profiling of protein-to-AI-based compound systems to expedite drug discovery.

Clues to the Design of Aggregation-Resistant Insulin from Proline Scanning of Highly Amyloidogenic Peptides Derived from the N-Terminal Segment of the A-Chain.

Insulin aggregation poses a significant problem in pharmacology and medicine as it occurs during prolonged storage of the hormone and in vivo at insulin injection sites. We have recently shown that dominant forces driving the self-assembly of insulin fibrils are likely to arise from intermolecular interactions involving the N-terminal segment of the A-chain (ACC1-13). Here, we study how proline substitutions within the pilot GIVEQ sequence of this fragment affect its propensity to aggregate in both neutral and acidic environments. In a reasonable agreement with in silico prediction based on the Cordax algorithm, proline substitutions at positions 3, 4, and 5 turn out to be very effective in preventing aggregation according to thioflavin T-fluorescence-based kinetic assay, infrared spectroscopy, and atomic force microscopy (AFM). Since the valine and glutamate side chains within this segment are strongly involved in the interactions with the insulin receptor, we have focused on the possible implications of the Q → P substitution for insulin's stability and interactions with the receptor. To this end, comparative molecular dynamics (MD) simulations of the Q5P mutant and wild-type insulin were carried out for both free and receptor-bound (site 1) monomers. The results point to a mild destabilization of the mutant vis à vis the wild-type monomer, as well as partial preservation of key contacts in the complex between Q5P insulin and the receptor. We discuss the implications of these findings in the context of the design of aggregation-resistant insulin analogues retaining hormonal activity.

Improved Approach for ab Initio Calculations of Rate Coefficients for Secondary Reactions in Acrylate Free-Radical Polymerization.

Secondary reactions in radical polymerization pose a challenge when creating kinetic models for predicting polymer structures. Despite the high impact of these reactions in the polymer structure, their effects are difficult to isolate and measure to produce kinetic data. To this end, we used solvation-corrected M06-2X/6-311+G(d,p) ab initio calculations to predict a complete and consistent data set of intrinsic rate coefficients of the secondary reactions in acrylate radical polymerization, including backbiting, β-scission, radical migration, macromonomer propagation, mid-chain radical propagation, chain transfer to monomer and chain transfer to polymer. Two new approaches towards computationally predicting rate coefficients for secondary reactions are proposed: (i) explicit accounting for all possible enantiomers for reactions involving optically active centers; (ii) imposing reduced flexibility if the reaction center is in the middle of the polymer chain. The accuracy and reliability of the ab initio predictions were benchmarked against experimental data via kinetic Monte Carlo simulations under three sufficiently different experimental conditions: a high-frequency modulated polymerization process in the transient regime, a low-frequency modulated process in the sliding regime at both low and high temperatures and a degradation process in the absence of free monomers. The complete and consistent ab initio data set compiled in this work predicts a good agreement when benchmarked via kMC simulations against experimental data, which is a technique never used before for computational chemistry. The simulation results show that these two newly proposed approaches are promising for bridging the gap between experimental and computational chemistry methods in polymer reaction engineering.

Comparative analysis of cytotoxicity effects of two denture hard lining materials on human gingival fibroblasts: an in vitro study

BackgroundThe objective of this study was to compare the cytotoxicity of TDV and Rebase II denture hard liners on human gingival fibroblasts, aiming to address issues associated with incomplete polymerization and free monomers that affect material properties. MethodsSeventy-two specimens (24 each of TDV, Rebase II, and controls) were prepared under aseptic conditions according to factory instructions. Cytotoxicity was determined using the MTT test with methyl tetrazolium salt added to the cell culture medium. A two-way ANOVA and a post-hoc Tukey test was used to evaluate the results of incubation before mitochondrial activity was measured using Multiscan spectrophotometry (570 nm). ResultsThere were significant differences in cell viability between the groups after 24 hours (P < 0.001), with TDV having higher viability than Rebase II. The difference between Rebase II and TDV, however, was not significant at 48 and 96 hours (P > 0.131). At 24 hours, Rebase II exhibited significantly lower viability than TDV liner, with a significant difference between the two groups (P = 0.001). ConclusionDue to the maximum monomer release in the early hours of incubation, the amount of cytotoxicity decreased with increasing incubation time.

A mini-review on different polymerization protocols for resin-based dental composites

Biocompatibility is one of the major prerequisites for safe clinical application of materials. Dental resin composites may release their components into oral environment, which can lead to adverse reactions. Several studies have identified that many organic components of composites resin, such as bisphenol-A-glycidyl-methacrylate (Bis-GMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA) and 2-hydroxyethyl methacrylate (HEMA) show a cytotoxic profile. Cytotoxicity is mainly sustained by free monomers released after polymerization process. Direct restorations are polymerized at body temperature by visible light emitting lamps, but the conversion from monomer to polymer after light-curing is never complete. To improve the degree of conversion of resin-based composites, additional curing protocols performed at increased temperatures, such as heat-curing, can be employed. Polymerization reaction plays a key role in the conversion of the free monomers into polymers and resin-based composites with high degree of conversion might show higher biocompatibility. The aim of this mini-review is to report current knowledge about the cytotoxicity of different composite resins, cured in two different ways. Further studies are necessary to better understand the relationship between the cytotoxicity and the degree of polymerization of resin-based composites.

GFN-xTB-Based Computations Provide Comprehensive Insights into Emulsion Radiation-Induced Graft Polymerization.

In this article, a deep insight into emulsion radiation-induced graft polymerization (RIGP) was obtained by computing explicit solvation free energies, conformational entropy, monomer radius and dipole moments with the state-of-the-art Conformer-Rotamer Ensemble Sampling Tool (CREST) package primarily at semiempirical GFN-xTB level. By leveraging the robustness of the CREST package, above parameters provided dynamic nature of methacrylate monomers with the consideration of realistic emulsion conditions. With the chemical and physical importance of the above results, CREST-determined explanatory variables sufficiently led to the building of the prediction models for the RIGP of methacrylate monomers. The machine learning model building resulted in effective reactivity predictions and unveiled important factors for the radiation-induced graft polymerization in a chemically interpretable fashion.

Crystal growth, HOMO-LUMO engineering and charge-transfer emission of TCNB-based donor-acceptor cocrystals

Using carbazole (CARB), dibenzothiophene (DBZP) and dibenzofuran (DBZF) as electron donors, 1,2,4,5-tetracyanobenzene (TCNB) as electron acceptor, three typical types of luminescent organic cocrystals were synthesized by a simple supramolecular assembly strategy. The cocrystals exhibit interesting optical properties for its charge transfer (CT) interactions. Meanwhile, a series of three-component (CARB)x (DBZP)1-x (TCNB) crystalline microtubes comprising organic CT interactions have been prepared by the self-assembly with poor solvent co-precipitating method. DFT calculations were used to predict the CT interactions and the binding patterns of donor and acceptor, which suggest that the CT interactions can largely influence the energy level and orbital distributions. Moreover, the SXRD analyses verified the cocrystals are constructed by π-π stacking with a face-to-face model. The solid-state cocrystals and microtubes were well characterized by PXRD, UV absorption spectra, emission spectra, fluorescence lifetime and quantum yield analyses. The obvious red-shift in UV–vis absorption spectra and emission spectra with respect to the free monomer indicate the formation of CT interactions. The emission colors of the mixed microtubes can be tailored from green to orange as well as associated photophysical properties with the increasing of dopant concentrations. Therefore, by the combination of experimental and theoretical studies on the cocrystals and microtubes, this work not only reports the new types of crystalline micro-nano materials, but also provides an in-depth understanding of the relationship between structure and fluorescence effect.

Oppositely charged surfactants and nanoparticles at the air-water interface: Influence of surfactant to nanoparticle ratio

HypothesisThe interactions between oppositely charged nanoparticles and surfactants can significantly influence the interfacial properties of the system. Traditionally, in the study of such systems, the nanoparticle concentration is varied while the surfactant concentration is kept constant, or vice versa. However, we believe that a defined variation of both components' concentration is necessary to accurately assess their effects on the interfacial properties of the system. We argue that the effect of nanoparticle-surfactant complexes can only be properly evaluated by keeping the surfactant to nanoparticle ratio constant. ExperimentsZeta potential, dynamic light scattering, high amplitude surface pressure and surface tension measurements are employed synergistically to characterize the interfacial properties of the nanoparticle-surfactant system. Interferometric experiments are performed to highlight the effect of surface concentration on the stability of thin liquid films. FindingsThe interfacial properties of surfactant/nanoparticle mixtures are primarily determined by the surfactant/nanoparticle ratio. Below a certain ratio, free surfactant molecules are removed from the solution by the formation of surfactant-nanoparticle complexes. Surprisingly, even though the concentration and hydrophobicity of these complexes do not seem to have a noticeable impact on the surface tension, they do significantly affect the rheological properties of the interface. Above this ratio, free surfactant monomers and nanoparticle-surfactant complexes coexist and can co-adsorb at the interface, changing both the interfacial tension and the interfacial rheology, and thus, for example, the foamability and foam stability of the system.

Drug Aggregation of Sparingly-Soluble Ionizable Drugs: Molecular Dynamics Simulations of Papaverine and Prostaglandin F2α.

Aggregation in aqueous solution can have important implications on both the in vivo exposure of a drug and its pharmaceutical manufacturability. However, the drug aggregates formed can be very small and, thus, difficult to interrogate experimentally. On the other hand, at higher supersaturations where larger aggregates are supported, the chemical system is inherently metastable and therefore likewise challenging to study from an experimental standpoint. Understanding aggregation behavior is further complicated in the case of ionizable drugs where, unlike neutral compounds, there can be uncertainty in the kinds of drug molecules (i.e., charged, neutral, or both) that become incorporated into various clusters, particularly at pH values near the pKa. In this paper, we apply physics-based all-atom molecular dynamics (MD) simulations to study aggregation in the weakly basic drug papaverine and in the weakly acidic drug prostaglandin F2α. We employ in silico tools to construct simulation workflows and comprehensive cluster analysis protocols to elucidate the size distributions and dynamics of the drug aggregates formed at both an experimentally relevant concentration and at high supersaturation. We build on a previously published treatment [Solubility of sparingly soluble ionizable drugs. Adv. Drug Deliv. Rev. 2007, 59, 568-590, DOI: 10.1016/j.addr.2007.05.008] to translate the predicted aggregate distributions of each ionized drug into corresponding pH-solubility curves that can be compared directly to experiment. Our findings show that the assumption of a single predominant (charged) aggregate can be misleading in interpreting experimental pH-solubility curves, as it does not adequately reflect the rich diversity revealed in our simulations. Beyond not accounting for the distribution of ionized drug-containing clusters actually observed in solution, for both drugs we find evidence that neutral drug molecules can also participate in the aggregation phenomena. Notably, we observe that many drug molecules remain as free monomers in solution even under simulated conditions designed to mimic those where there is significant deviation of the experimental pH-solubility curve from the Henderson-Hasselbalch (H-H) equation, often taken to be a clear signpost of drug aggregation.

Nanocompartment-confined polymerization in living systems

Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers, the existence of complicated intracorporal interferences, and the demand for extra external stimulations hinder their further biological applications. Herein, a nanocompartment-confined strategy that provides a confined and secluded environment for monomer enrichment and isolation is developed to achieve high polymerization efficiency, reduce the interference from external environment, and realize broad-spectrum polymerizations in living systems. For exogenous photopolymerization, the light-mediated free-radical polymerization of sodium 4-styrenesulfonate induces a 2.7-fold increase in the reaction rate with the protection of a confined environment. For endogenous hydrogen peroxide-responsive polymerization, p‑aminodiphenylamine hydrochloride embedded in a nanocompartment not only performs a 6.4-fold higher reaction rate than that of free monomers, but also activates an effective second near-infrared photoacoustic imaging-guided photothermal immunotherapy at tumor sites. This nanocompartment-confined strategy breaks the shackles of conventional polymerization, providing a universal platform for in vivo synthesis of polymers with diverse structures and functions.

Enhancing Nanofiltration Selectivity of Metal-Organic Framework Membranes via a Confined Interfacial Polymerization Strategy.

Development of well-constructed metal-organic framework (MOF) membranes can bring about breakthroughs in nanofiltration (NF) performance for water treatment applications, while the relatively loose structures and inevitable defects usually cause low rejection capacity of MOF membranes. Herein, a confined interfacial polymerization (CIP) method is showcased to synthesize polyamide (PA)-modified NF membranes with MOF nanosheets as the building blocks, yielding a stepwise transition from two-dimensional (2D) MOF membranes to polyamide NF membranes. The CIP process was regulated by adjusting the loading amount of piperazine (PIP)-grafted MOF nanosheets on substrates and the additional content of free PIP monomers distributed among the nanosheets, followed by the reaction with trimesoyl chloride in the organic phase. The prepared optimal membrane exhibited a high Na2SO4 rejection of 98.4% with a satisfactory water permeance of 37.4 L·m-2·h-1·bar-1, which could be achieved by neither the pristine 2D MOF membranes nor the PA membranes containing the MOF nanosheets as the conventional interlayer. The PA-modified MOF membrane also displayed superior stability and enhanced antifouling ability. This CIP strategy provides a novel avenue to develop efficient MOF-based NF membranes with high ion-sieving separation performance for water treatment.

Multimodal investigation of electronic transport in PTMA and its impact on organic radical battery performance

Organic radical batteries (ORBs) represent a viable pathway to a more sustainable energy storage technology compared to conventional Li-ion batteries. For further materials and cell development towards competitive energy and power densities, a deeper understanding of electron transport and conductivity in organic radical polymer cathodes is required. Such electron transport is characterised by electron hopping processes, which depend on the presence of closely spaced hopping sites. Using a combination of electrochemical, electron paramagnetic resonance (EPR) spectroscopic, and theoretical molecular dynamics as well as density functional theory modelling techniques, we explored how compositional characteristics of cross-linked poly(2,2,6,6-tetramethyl-1-piperidinyloxy-4-yl methacrylate) (PTMA) polymers govern electron hopping and rationalise their impact on ORB performance. Electrochemistry and EPR spectroscopy not only show a correlation between capacity and the total number of radicals in an ORB using a PTMA cathode, but also indicates that the state-of-health degrades about twice as fast if the amount of radical is reduced by 15%. The presence of up to 3% free monomer radicals did not improve fast charging capabilities. Pulsed EPR indicated that these radicals readily dissolve into the electrolyte but a direct effect on battery degradation could not be shown. However, a qualitative impact cannot be excluded either. The work further illustrates that nitroxide units have a high affinity to the carbon black conductive additive, indicating the possibility of its participation in electron hopping. At the same time, the polymers attempt to adopt a compact conformation to increase radical–radical contact. Hence, a kinetic competition exists, which might gradually be altered towards a thermodynamically more stable configuration by repeated cycling, yet further investigations are required for its characterisation.

Temporal control by cofactors prevents kinetic trapping in retroviral Gag lattice assembly

For retroviruses like HIV to proliferate, they must form virions shaped by the self-assembly of Gag polyproteins into a rigid lattice. This immature Gag lattice has been structurally characterized and reconstituted in vitro, revealing the sensitivity of lattice assembly to multiple cofactors. Due to this sensitivity, the energetic criterion for forming stable lattices is unknown, as are their corresponding rates. Here, we use a reaction-diffusion model designed from the cryo-ET structure of the immature Gag lattice to map a phase diagram of assembly outcomes controlled by experimentally constrained rates and free energies, over experimentally relevant timescales. We find that productive assembly of complete lattices in bulk solution is extraordinarily difficult due to the large size of this ∼3700 monomer complex. Multiple Gag lattices nucleate before growth can complete, resulting in loss of free monomers and frequent kinetic trapping. We therefore derive a time-dependent protocol to titrate or “activate” the Gag monomers slowly within the solution volume, mimicking the biological roles of cofactors. This general strategy works remarkably well, yielding productive growth of self-assembled lattices for multiple interaction strengths and binding rates. By comparing to the in vitro assembly kinetics, we can estimate bounds on rates of Gag binding to Gag and the cellular cofactor IP6. Our results show that Gag binding to IP6 can provide the additional time delay necessary to support smooth growth of the immature lattice with relatively fast assembly kinetics, mostly avoiding kinetic traps. Our work provides a foundation for predicting and disrupting formation of the immature Gag lattice via targeting specific protein-protein binding interactions.

Aggregation and partitioning of amyloid peptide fragments in the presence of a lipid bilayer: A coarse grained molecular dynamics study

Amyloidogenicity and toxicity of amyloid peptides have been linked to the peptide aggregation and interactions with lipid bilayers. In this work we used the coarse grained MARTINI model to study the aggregation and partitioning of amyloid peptide fragments Aβ(1–28) and Aβ(25–35) in the presence of a dipalmitoylphosphatidylcholine bilayer. We explored the peptide aggregation starting from three initial spatial arrangements where free monomers were placed in solution outside the membrane, at the membrane-solution interface, or in the membrane. We found that Aβ(1–28) and Aβ(25–35) interact with the bilayer quite differently. The Aβ(1–28) fragments show strong peptide-peptide and peptide-lipid interactions leading to irreversible aggregation where the aggregates stay confined to their initial spatial location. The Aβ(25–35) fragments show weaker peptide-peptide and peptide-lipid interaction leading to reversible aggregation and accumulation at the membrane-solution interface irrespective of their initial spatial arrangement. Those findings can be explained in terms of the shape of the potential of mean force for the single-peptide translocation across the membrane.