The surface tension of Martini 3 water mixtures.

The Martini model, a coarse-grained forcefield for biomolecular simulations, has experienced a vast increase in popularity in the past decade. Its building-block approach balances computational efficiency with high chemical specificity, enabling the simulation of organic and inorganic molecules. The modeling of coarse-grained beads as Lennard-Jones particles poses challenges for the accurate reproduction of liquid-vapor interfacial properties, which are crucial in various applications, especially in the case of water. The latest version of the forcefield introduces refined interaction parameters for water beads, tackling the well-known artifact of Martini water freezing at room temperature. In addition, multiple sizes of water beads are available for simulating the solvation of small cavities, including the smallest pockets of proteins. This work focuses on studying the interfacial properties of Martini water, including surface tension and surface thickness. Employing the test-area method, we systematically compute the liquid-vapor surface tension across various combinations of water bead sizes and for temperatures from 300 to 350 K. These findings are of interest to the Martini community as they allow users to account for the low interfacial tension of Martini water by properly adjusting observables computed via coarse-grained simulations to allow for accurate matching against all-atom or experimental results. Surface tension data are also interpreted in terms of local enrichment of the various mixture components at the liquid-vapor interface by means of Gibbs' adsorption formalism. Finally, the critical scaling of the Martini surface tension with temperature is reported to be consistent with the critical exponent of the 3D Ising universality class.

Cholesterol-Containing Liposomes Decorated With Au Nanoparticles as Minimal Tunable Fusion Machinery.

Membrane fusion is essential for the basal functionality of eukaryotic cells. In physiological conditions, fusion events are regulated by a wide range of specialized proteins, operating with finely tuned local lipid composition and ionic environment. Fusogenic proteins, assisted by membrane cholesterol and calcium ions, provide the mechanical energy necessary to achieve vesicle fusion in neuromediator release. Similar cooperative effects must be explored when considering synthetic approaches for controlled membrane fusion. We show that liposomes decorated with amphiphilic Au nanoparticles (AuLips) can act as minimal tunable fusion machinery. AuLips fusion is triggered by divalent ions, while the number of fusion events dramatically changes with, and can be finely tuned by, the liposome cholesterol content. We combine quartz-crystal-microbalance with dissipation monitoring (QCM-D), fluorescence assays, and small-angle X-ray scattering (SAXS) with molecular dynamics (MD) at coarse-grained (CG) resolution, revealing new mechanistic details on the fusogenic activity of amphiphilic Au nanoparticles (AuNPs) and demonstrating the ability of these synthetic nanomaterials to induce fusion regardless of the divalent ion used (Ca2+ or Mg2+ ). The results provide a novel contribution to developing new artificial fusogenic agents for next-generation biomedical applications that require tight control of the rate of fusion events (e.g., targeted drug delivery).

Correction: Development of a transferable coarse-grained model of polydimethylsiloxane.

Correction for 'Development of a transferable coarse-grained model of polydimethylsiloxane' by Sonia Cambiaso et al., Soft Matter, 2022, https://doi.org/10.1039/d2sm00939k.

Development of a transferable coarse-grained model of polydimethylsiloxane.

Polydimethylsiloxane (PDMS) is a popular silicon-based polymer with advanced applications in microfluidics and nanocomposites. The slow dynamics of polymer chains in such complex systems hinders molecular dynamics investigations based on all atom force fields. This limitation can be overcome by exploiting finely tuned coarse-grained (CG) models. This paper develops a transferable CG model of PDMS, compatible with the recent Martini 3 force field, using structural and thermodynamic properties as targets in the parametrization, including a vast set of experimental free energies of transfer. We validate the model transferability by reproducing the correct scaling laws for the PDMS gyration radius in the melt and good and bad solvents. We successfully test the model by reproducing the wetting behavior of water and acetonitrile on PDMS and the phase behavior of a PDMS-peptide triblock copolymer system. This work sets the stage for computational studies involving the interaction between PDMS and many synthetic and biological molecules modeled within the Martini framework.

Discordant Supramolecular Fibres Reversibly Depolymerised by Temperature and Light.

Synthetic stimuli responsive supramolecular polymers attract increasing interest for their ability to mimic the unique properties of natural assemblies. Here we focus on the well-studied benzene-1,3,5-tricarboxamide (BTA) motif, and substitute it with two (S)-3,7-dimethyloctyl groups and an azobenzene photoswitch. We demonstrate the UV (λ=365 nm) induced depolymerisation of the helical hydrogen-bonded polymers in methylcyclohexane (MCH) through circular dichroism and UV-vis spectroscopy in dilute solution (15 µm), and NMR and iPAINT super-resolution microscopy in concentrated solution (300 µm). The superstructure can be regenerated after thermal depolymerization, whilst repeated depolymerisation can be reversed without degradation by irradiating at λ=455 nm. Molecular dynamics simulations show that the most energetically favourable configuration for these polymers in MCH is a left-handed helical network of hydrogen-bonds between the BTA cores surrounded by two right-handed helices of azobenzenes. The responsiveness to two orthogonal triggers across a broad concentration range holds promise for use in, for example, photo-responsive gelation.

Self-Sorted, Random, and Block Supramolecular Copolymers via Sequence Controlled, Multicomponent Self-Assembly.

Multicomponent supramolecular copolymerization promises to construct complex nanostructures with emergent properties. However, even with two monomeric components, various possible outcomes such as self-sorted supramolecular homopolymers, a random (statistical) supramolecular copolymer, an alternate supramolecular copolymer, or a complex supramolecular block copolymer can occur, determined by their intermolecular interactions and monomer exchange dynamics and hence structural prediction is extremely challenging. Herein, we target this challenge and demonstrate unprecedented two-component sequence controlled supramolecular copolymerization by manipulating thermodynamic and kinetic routes in the pathway complexity of self-assembly of the constitutive monomers. Extensive molecular dynamics simulations provided useful mechanistic insights into the monomer exchange rates and free energy of interactions between the monomers that dictate the self-assembly pathway and sequence. The fluorescent nature of core-substituted naphthalene diimide monomers has been further utilized to characterize the three sequences via Structured Illumination Microscopy (SIM).

Biomimetic Synthesis of Sub-20 nm Covalent Organic Frameworks in Water.

Covalent organic frameworks (COFs) are commonly synthesized under harsh conditions yielding unprocessable powders. Control in their crystallization process and growth has been limited to studies conducted in hazardous organic solvents. Herein, we report a one-pot synthetic method that yields stable aqueous colloidal solutions of sub-20 nm crystalline imine-based COF particles at room temperature and ambient pressure. Additionally, through the combination of experimental and computational studies, we investigated the mechanisms and forces underlying the formation of such imine-based COF colloids in water. Further, we show that our method can be used to process the colloidal solution into 2D and 3D COF shapes as well as to generate a COF ink that can be directly printed onto surfaces. These findings should open new vistas in COF chemistry, enabling new application areas.

Molecular photoswitches mediating the strain-driven disassembly of supramolecular tubules.

Chemists have created molecular machines and switches with specific mechanical responses that were typically demonstrated in solution, where mechanically relevant motion is dissipated in the Brownian storm. The next challenge consists of designing specific mechanisms through which the action of individual molecules is transmitted to a supramolecular architecture, with a sense of directionality. Cellular microtubules are capable of meeting such a challenge. While their capacity to generate pushing forces by ratcheting growth is well known, conversely these versatile machines can also pull microscopic objects apart through a burst of their rigid tubular structure. One essential feature of this disassembling mechanism is the accumulation of strain in the tubules, which develops when tubulin dimers change shape, triggered by a hydrolysis event. We envision a strategy toward supramolecular machines generating directional pulling forces by harnessing the mechanically purposeful motion of molecular switches in supramolecular tubules. Here, we report on wholly synthetic, water-soluble, and chiral tubules that incorporate photoswitchable building blocks in their supramolecular architecture. Under illumination, these tubules display a nonlinear operation mode, by which light is transformed into units of strain by the shape changes of individual switches, until a threshold is reached and the tubules unleash the strain energy. The operation of this wholly synthetic and stripped-down system compares to the conformational wave by which cellular microtubules disassemble. Additionally, atomistic simulations provide molecular insight into how strain accumulates to induce destabilization. Our findings pave the way toward supramolecular machines that would photogenerate pulling forces, at the nanoscale and beyond.

A Block Supramolecular Polymer and Its Kinetically Enhanced Stability.

Biomolecular systems serve as an inspiration for the creation of multicomponent synthetic supramolecular systems that can be utilized to develop functional materials with complexity. However, supramolecular systems rapidly reach an equilibrium state through dynamic and reversible noncovalent bonds, resulting in a disorganized mixture of components rather than a system in which individual components function cooperatively and/or independently. Thus, efficient synthetic strategies and characterization methods for intricate multicomponent supramolecular assemblies need to be developed. Herein, we report the synthesis of porphyrin-based supramolecular polymers (SPs) in which two distinct block segments consisting of different metal porphyrins are connected: i.e., block supramolecular polymers (BSPs). BSPs with a controlled length and narrow polydispersity were achieved through seeded-growth by a solvent mixing protocol. Interestingly, the block structure permitted the SP as an inner block to coexist with a reagent that was otherwise incompatible with the SP alone. We infer that the inner SP block is compartmentalized in the block structure and endowed with the kinetic stability. Molecular simulations revealed that monomer exchange occurs from the termini of the SP, which corroborated the enhanced stability of the BSP. These results are expected to pave the way for the design of more complex multicomponent supramolecular systems.

Nitrobenzoxadiazole-Appended Cell Membrane Modifiers for Efficient Optoporation with Noncoherent Light.

FLNBD-BAMPEG2k, bearing a nitrobenzoxadiazole (NBD) unit and an oleyl terminus conjugated via a poly(ethylene glycol) (PEG) spacer ( Mn = 2,000), was designed to fluorescently label cell membranes by docking its hydrophobic oleyl terminus. During laser scanning microscopy in a minimal essential medium (MEM), human hepatocellular carcinoma Hep3B cells labeled with FLNBD-BAMPEG2k appeared to undergo optoporation at their plasma membrane. We confirmed this unprecedented possibility by a series of cellular uptake experiments using negatively charged and therefore membrane-impermeable quantum dots (QDs; Dh = 4.7 nm). Detailed studies indicated that the photoexcited NBD unit can generate singlet oxygen (1O2), which oxidizes the constituent phospholipids to transiently deteriorate the cell membrane. Reference membrane modifiers FLNBD-Oleyl and FLNBD-BAMPEG8k having shorter or longer hydrophilic spacers between the NBD and oleyl units showed a little or substantially no optoporation. For understanding these results, one must consider the following contradictory factors: (1) The photosensitized 1O2 generation efficiently occurs only when the NBD unit is in aqueous media, and (2) the lifetime of 1O2 in aqueous media is very short (3.0-3.5 µs). As supported experimentally and computationally, the hydrophilic spacer length of FLNBD-BAMPEG2k is optimal for compromising these factors. Further to note, the optoporation using FLNBD-BAMPEG2k is not accompanied by cytotoxicity.

Three-Dimensional Directionality Is a Pivotal Structural Feature for the Bioactivity of Azabisphosphonate-Capped Poly(PhosphorHydrazone) Nanodrug Dendrimers.

Dendrimers are nanosized, nonlinear, hyperbranched polymers whose overall 3D shape is key for their biological activity. Poly(PhosphorHydrazone) (PPH) dendrimers capped with aza-bisphosphonate (ABP) end groups are known to have anti-inflammatory properties enabling the control of inflammatory diseases in different mouse models. Here we screen the anti-inflammatory activity of a series of PPH dendrimers bearing between 2 and 16 ABP end groups in a mouse model of arthritis and confront the biological results with atomistic simulations of the dendrimers. We show that only the PPH dendrimers capped with 10 and 12 ABP end groups can control the flare of the inflammatory disease. All-atom accelerated molecular dynamics simulations show that dendrimers with a low number of ABP end groups are directional but highly flexible/dynamic and have thereby limited efficiency in establishing multivalent interactions. The largest dendrimer appears as nondirectional, having 16 ABP end groups forming patches all over the dendrimer surface. Conversely, intermediate dendrimers having 10 or 12 ABP end groups reach the best compromise between the number of surface groups and their stable directional gathering, a real maximization of multivalency.

Supramolecular Copolymerization as a Strategy to Control the Stability of Self-Assembled Nanofibers.

A major challenge in supramolecular polymerization is controlling the stability of the polymers formed, that is, controlling the rate of monomer exchange in the equilibrium between monomer and polymer. The exchange dynamics of supramolecular polymers based on benzene-1,3,5-tricarboxamide (BTA) can be regulated by copolymerizing molecules with dendronized (dBTA) and linear (nBTA) ethylene glycol-based water-soluble side chains. Whereas nBTAs form long nanofibers in water, dBTAs do not polymerize, forming instead small spherical aggregates. The copolymerization of the two BTAs results in long nanofibers. The exchange dynamics of both the BTA monomers in the copolymer are significantly slowed down in the mixed systems, leading to a more stable copolymer, while the morphology and spectroscopic signature of the copolymers are identical to that of nBTA homopolymer. This copolymerization is the supramolecular counterpart of styrene/ maleic anhydride copolymerization.

Aggregation of binary colloidal suspensions on attractive walls.

The adsorption of colloidal particles from a suspension on a solid surface is of fundamental importance to many physical and biological systems. In this work, Brownian Dynamics simulations are performed to study the aggregation in a suspension of oppositely charged colloidal particles in the presence of an attractive wall. For sufficiently strong attractions, the wall alters the microstructure of the aggregates so that B2 (CsCl-type) structures are more likely obtained instead of B1 (NaCl-type) structures. The probability of forming either B1 or B2 crystallites depends also on the inverse interaction range κa. Suspensions with small κa are more likely to form B2 crystals than suspensions with larger κa, even if the energetic stability of the B2 phase decreases with decreasing κa. The mechanisms underlying this aggregation and crystallization behaviour are analyzed in detail.

Calculating the free energy of transfer of small solutes into a model lipid membrane: Comparison between metadynamics and umbrella sampling.

We compare the performance of two well-established computational algorithms for the calculation of free-energy landscapes of biomolecular systems, umbrella sampling and metadynamics. We look at benchmark systems composed of polyethylene and polypropylene oligomers interacting with lipid (phosphatidylcholine) membranes, aiming at the calculation of the oligomer water-membrane free energy of transfer. We model our test systems at two different levels of description, united-atom and coarse-grained. We provide optimized parameters for the two methods at both resolutions. We devote special attention to the analysis of statistical errors in the two different methods and propose a general procedure for the error estimation in metadynamics simulations. Metadynamics and umbrella sampling yield the same estimates for the water-membrane free energy profile, but metadynamics can be more efficient, providing lower statistical uncertainties within the same simulation time.

Chemical ordering in magic-size Ag-Pd nanoparticles.

Chemical ordering in magic-size Ag-Pd nanoalloys is studied by means of global optimization searches within an atomistic potential developed on the basis of density functional theory calculations. Ag-rich, intermediate and Pd-rich compositions are considered for fcc truncated octahedral, icosahedral and decahedral geometric structures. Besides a surface enrichment in Ag, we find a significant subsurface enrichment in Pd, which persists to quite high temperatures as verified by Monte Carlo simulations. This subsurface Pd enrichment is stronger in nanoparticles than in bulk systems and is rationalized in terms of the energetics of the inclusion of a single Pd impurity in an Ag host nanoparticle. Our results can be relevant to the understanding of the catalytic activity of Ag-Pd nanoparticles in those reactions in which subsurface sites play a role.

Nanoparticle-induced biomembrane fusion: unraveling the effect of core size on stalk formation.

Membrane fusion in vitro is a strategy to load model or cell-derived vesicles with proteins, drugs, and genetic materials for theranostic applications. It is thus crucial to develop strategies to control the fusion process, also through synthetic fusogenic agents. Ligand-protected, membrane-penetrating gold nanoparticles (Au NPs) can facilitate membrane fusion, but the molecular mechanisms remain unresolved. Here, we tackle NP-induced stalk formation using a coarse-grained molecular dynamics approach and enhanced sampling techniques. We show that smaller (2 nm in diameter) NPs lead to a lower free energy barrier and higher stalk stability than larger NPs (4 nm). We demonstrate that this difference is due to a different ligand conformational freedom, which in turn depends on the Au core curvature. Our study provides precious insights into the mechanisms underlying NP-mediated membrane fusion, while our computational approach is general and applicable to studying stalk formation caused by other fusogenic agents.

Dumbbells, chains, and ribbons: anisotropic self-assembly of isotropic nanoparticles.

Functionalizing the surface of metal nanoparticles can assure their stability in solution or mediate their self-assembly into aggregates with controlled shapes. Here we present a computational study of the colloidal aggregation of gold nanoparticles (Au NPs) isotropically functionalized by a mixture of charged and hydrophobic ligands. We show that, by varying the relative proportion of the two ligands, the NPs form anisotropic aggregates with markedly different topologies: dumbbells, chains, or ribbons. In all cases, two kinds of connections keep the aggregates together: hydrophobic bonds and ion bridges. We show that the anisotropy of the aggregates derives from the NP shell reshaping due to the formation of the hydrophobic links, while ion bridges are accountable for the "secondary structure" of the aggregates. Our findings provide a general physical principle that can also be exploited in different self-assembled systems: anisotropic/directional aggregation can be achieved starting from isotropic objects with a soft, deformable surface.

Protein Content in the Diet Influences Growth and Diarrhea in Weaning Piglets.

The aim of this research has been to assess the effect of the dietary protein level on piglet growth and post-weaning diarrhea (PWD) incidence. Piglet fecal microbiota and feces composition were also assessed. The experiment was carried out on 144 weaned piglets (Duroc × Large White; 72 piglets per treatment) and lasted from weaning (at 25 days of age) until the end of the post-weaning phase (at 95 days). Two dietary protein levels were compared: high (HP; 17.5% crude protein on average, during the experiment) and low (LP; 15.5% on average). Lower (p < 0.01) average daily gain and feed conversion ratio were observed in LP piglets in the first growth phase. However, at the end of the post-weaning period, the growth parameters were not significantly different in the two diets. Diarrhea scores were lower in piglets fed LP diets than in piglets fed HP diets (28.6% of the total vs. 71.4% in the HP piglets). Fibrobacteres, Proteobacteria, and Spirochaetes were more abundant in the feces of the piglets fed LP diets. Feces nitrogen content was lower in piglets fed LP diets. In conclusion, low protein levels in the diet can reduce the incidence of PWD while only marginally affecting growth parameters.

Amphiphilic Gold Nanoparticles: A Biomimetic Tool to Gain Mechanistic Insights into Peptide-Lipid Interactions.

Functional peptides are now widely used in a myriad of biomedical and clinical contexts, from cancer therapy and tumor targeting to the treatment of bacterial and viral infections. Underlying this diverse range of applications are the non-specific interactions that can occur between peptides and cell membranes, which, in many contexts, result in spontaneous internalization of the peptide within cells by avoiding energy-driven endocytosis. For this to occur, the amphipathicity and surface structural flexibility of the peptides play a crucial role and can be regulated by the presence of specific molecular residues that give rise to precise molecular events. Nevertheless, most of the mechanistic details regulating the encounter between peptides and the membranes of bacterial or animal cells are still poorly understood, thus greatly limiting the biomimetic potential of these therapeutic molecules. In this arena, finely engineered nanomaterials-such as small amphiphilic gold nanoparticles (AuNPs) protected by a mixed thiol monolayer-can provide a powerful tool for mimicking and investigating the physicochemical processes underlying peptide-lipid interactions. Within this perspective, we present here a critical review of membrane effects induced by both amphiphilic AuNPs and well-known amphiphilic peptide families, such as cell-penetrating peptides and antimicrobial peptides. Our discussion is focused particularly on the effects provoked on widely studied model cell membranes, such as supported lipid bilayers and lipid vesicles. Remarkable similarities in the peptide or nanoparticle membrane behavior are critically analyzed. Overall, our work provides an overview of the use of amphiphilic AuNPs as a highly promising tailor-made model to decipher the molecular events behind non-specific peptide-lipid interactions and highlights the main affinities observed both theoretically and experimentally. The knowledge resulting from this biomimetic approach could pave the way for the design of synthetic peptides with tailored functionalities for next-generation biomedical applications, such as highly efficient intracellular delivery systems.

Ion-bridges and lipids drive aggregation of same-charge nanoparticles on lipid membranes.

The control of the aggregation of biomedical nanoparticles (NP) in physiological conditions is crucial as clustering may change completely the way they interact with the biological environment. Here we show that Au nanoparticles, functionalized by an anionic, amphiphilic shell, spontaneously aggregate in fluid zwitterionic lipid bilayers. We use molecular dynamics and enhanced sampling techniques to disentangle the short-range and long-range driving forces of aggregation. At short inter-particle distances, ion-mediated, charge-charge interactions (ion bridging) stabilize the formation of large NP aggregates, as confirmed by cryo-electron microscopy. Lipid depletion and membrane curvature are the main membrane deformations driving long-range NP-NP attraction. Ion bridging, lipid depletion, and membrane curvature stem from the configurational flexibility of the nanoparticle shell. Our simulations show, more in general, that the aggregation of same-charge membrane inclusions can be expected as a result of intrinsically nanoscale effects taking place at the NP-NP and NP-bilayer soft interfaces.