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).

Emergence of Electric Fields at the Water-C12E6 Surfactant Interface.

We study the properties of the interface of water and the surfactant hexaethylene glycol monododecyl ether (C12E6) with a combination of heterodyne-detected vibrational sum frequency generation (HD-VSFG), Kelvin-probe measurements, and molecular dynamics (MD) simulations. We observe that the addition of the hydrogen-bonding surfactant C12E6, close to the critical micelle concentration (CMC), induces a drastic enhancement in the hydrogen bond strength of the water molecules close to the interface, as well as a flip in their net orientation. The mutual orientation of the water and C12E6 molecules leads to the emergence of a broad (∼3 nm) interface with a large electric field of ∼1 V/nm, as evidenced by the Kelvin-probe measurements and MD simulations. Our findings may open the door for the design of novel electric-field-tuned catalytic and light-harvesting systems anchored at the water-surfactant-air interface.

Amyloid and membrane complexity: The toxic interplay revealed by AFM.

Lipid membranes play a fundamental role in the pathological development of protein misfolding diseases. Several pieces of evidence suggest that the lipid membrane could act as a catalytic surface for protein aggregation. Furthermore, a leading theory indicates the interaction between the cell membrane and misfolded oligomer species as the responsible for cytotoxicity, hence, for neurodegeneration in disorders such as Alzheimer's and Parkinson's disease. The definition of the mechanisms that drive the interaction between pathological protein aggregates and plasma membrane is fundamental for the development of effective therapies for a large class of diseases. Atomic force microscopy (AFM) has been employed to study how amyloid aggregates affect the cell physiological properties. Considerable efforts were spent to characterize the interaction with model systems, i.e., planar supported lipid bilayers, but some works also addressed the problem directly on living cells. Here, an overview of the main works involving the use of the AFM on both model system and living cells will be provided. Different kind of approaches will be presented, as well as the main results derived from the AFM analysis.

Toxic HypF-N Oligomers Selectively Bind the Plasma Membrane to Impair Cell Adhesion Capability.

The deposition of fibrillar protein aggregates in human organs is the hallmark of several pathological states, including highly debilitating neurodegenerative disorders and systemic amyloidoses. It is widely accepted that small oligomers arising as intermediates in the aggregation process, released by fibrils, or growing in secondary nucleation steps are the cytotoxic entities in protein-misfolding diseases, notably neurodegenerative conditions. Increasing evidence indicates that cytotoxicity is triggered by the interaction between nanosized protein aggregates and cell membranes, even though little information on the molecular details of such interaction is presently available. In this work, we propose what is, to our knowledge, a new approach, based on the use of single-cell force spectroscopy applied to multifunctional substrates, to study the interaction between protein oligomers, cell membranes, and/or the extracellular matrix. We compared the interaction of single Chinese hamster ovary cells with two types of oligomers (toxic and nontoxic) grown from the N-terminal domain of the Escherichia coli protein HypF. We were able to quantify the affinity between both oligomer type and the cell membrane by measuring the mechanical work needed to detach the cells from the aggregates, and we could discriminate the contributions of the membrane lipid and protein fractions to such affinity. The fundamental role of the ganglioside GM1 in the membrane-oligomers interaction was also highlighted. Finally, we observed that the binding of toxic oligomers to the cell membrane significantly affects the functionality of adhesion molecules such as Arg-Gly-Asp binding integrins, and that this effect requires the presence of the negatively charged sialic acid moiety of GM1.

Photoinitiator-free 3D scaffolds fabricated by excimer laser photocuring.

Photoinitiator-free fabrication of poly(ethylene glycol) diacrylate (PEGDA) scaffolds is achieved using a novel three-dimensional (3D) printing method called mask projected excimer laser stereolithography (MPExSL). The spatial resolution of photoinitiator-free curing is suitable for 3D layer-by-layer fabrication with a single layer thickness well controllable at tens to hundreds of microns using 248 nm wavelength for the irradiation. The photoinitiator-free scaffolds are superior compared to their counterparts fabricated by using photoinitiator molecules, showing a higher level of biocompatibility. A release of toxic chemicals from the photoinitiator containing scaffolds is proven by cell proliferation tests. In contrast, no toxic release is found from the photoinitiator-free scaffolds, resulting in the very same level of cell proliferation as the control sample. The demonstration of photoinitiator-free PEGDA scaffolds enables the fabrication of 3D scaffolds with the highest level of biocompatibility for both in vitro and in vivo applications.

Specific Neuron Placement on Gold and Silicon Nitride-Patterned Substrates through a Two-Step Functionalization Method.

The control of neuron-substrate adhesion has been always a challenge for fabricating neuron-based cell chips and in particular for multielectrode array (MEA) devices, which warrants the investigation of the electrophysiological activity of neuronal networks. The recent introduction of high-density chips based on the complementary metal oxide semiconductor (CMOS) technology, integrating thousands of electrodes, improved the possibility to sense large networks and raised the challenge to develop newly adapted functionalization techniques to further increase neuron electrode localization to avoid the positioning of cells out of the recording area. Here, we present a simple and straightforward chemical functionalization method that leads to the precise and exclusive positioning of the neural cell bodies onto modified electrodes and inhibits, at the same time, cellular adhesion in the surrounding insulator areas. Different from other approaches, this technique does not require any adhesion molecule as well as complex patterning technique such as µ-contact printing. The functionalization was first optimized on gold (Au) and silicon nitride (Si3N4)-patterned surfaces. The procedure consisted of the introduction of a passivating layer of hydrophobic silane molecules (propyltriethoxysilane [PTES]) followed by a treatment of the Au surface using 11-amino-1-undecanethiol hydrochloride (AT). On model substrates, well-ordered neural networks and an optimal coupling between a single neuron and single micrometric functionalized Au surface were achieved. In addition, we presented the preliminary results of this functionalization method directly applied on a CMOS-MEA: the electrical spontaneous spiking and bursting activities of the network recorded for up to 4 weeks demonstrate an excellent and stable neural adhesion and functional behavior comparable with what expected using a standard adhesion factor, such as polylysine or laminin, thus demonstrating that this procedure can be considered a good starting point to develop alternatives to the traditional chip coatings to provide selective and specific neuron-substrate adhesion.

PEGylated gold nanorods as optical trackers for biomedical applications: an in vivo and in vitro comparative study.

Gold nanorods (AuNRs) are eligible for a variety of biological applications including cell imaging, sensing, and photothermal therapy thanks to their optical properties. The aim of this work is to show how AuNRs could be employed as non-photobleachable optical contrast agents for biomedical applications. In order to demonstrate the feasibility of their use as optical trackers, we employed two-photon emission confocal microscopy on cells incubated with PEGylated AuNRs. Remarkably, AuNRs were localized mostly in the perinuclear zone and microscopy characterization showed the presence of a considerable number of rods inside cell nuclei. Furthermore, we estimated the toxicity and the efficiency of cellular uptake of the PEGylated AuNRs as a function of administered dose on HeLa/3T3 cell lines and on zebrafish during development, employed as an in vivo model. Eventually, we observed good agreement between in vivo and in vitro experiments. The employed AuNRs were prepared through a photochemical protocol here improved by tuning the amount of the cationic surfactant cetyltrimethylammonium bromide for the achievement of AuNRs at two different aspect ratios. Furthermore we also investigated if the AuNR aspect ratio influenced the toxicity and the efficiency of cellular uptake of the PEGylated AuNRs in HeLa/3T3 cell lines and in zebrafish embryos.

High resolution nanomechanical characterization of multi-domain model membranes by fast Force Volume.

Plasma membrane is a complex structure, mainly composed by lipids and proteins, which plays a pivotal role in cell metabolism by regulating its selective permeability to ions and molecules. According to the "raft hypothesis", lipids in the bilayer are not forming a structurally passive solvent, but are rather organized in specific domains, which present different structural and functional characteristics. The mechanical properties of the lipid part of plasma membrane have been recently characterized through Atomic Force Microscopy, by analyzing the features of force vs distance curves collected on supported lipid bilayers (SLBs). In case of lipid domains sizing from tens to hundreds of nanometers, which mimic in a good way the lateral organization of real membranes, a high lateral resolution and a large number of curves are often required for properly expressing the complexity of the system, with a consequent exponential growth of acquisition and processing time. In this paper we propose a method, based on a recently developed high speed Force Volume technique and on home-built data processing software, for the mechanical characterization of nanostructured SLBs. With our software we have been able to process data set composed by tens of thousands of curves, collected with a spatial resolution ranging from 8 to 40 nm/pixel. Multiparametric maps and distribution histograms produced by our analysis allowed identifying a specific behavior for each lipid phase in the investigated model membranes, even in presence of nanosized features.

Cholesterol drives aß(1-42) interaction with lipid rafts in model membranes.

The molecular mechanism at the basis of the neurodegenerative process related to Alzheimer's disease (AD) is triggered by the local composition of the neural plasma membrane. The role of cholesterol is controversial. In this investigation the interaction of the AD peptide amyloid-beta (1-42) with model membranes containing lipid rafts has been investigated by atomic force microscopy techniques. Supported lipid membranes made of phospholipids/sphingomyelin/cholesterol have been investigated as a function of the molar content of cholesterol, in a range spanning the phase diagram of the lipid system. The administration of amyloid-beta induced a phase reorganization of the lipid domains, when the cholesterol molar fraction was below 5%. At the same time, a mechanical destabilization and an appreciable thinning of the membrane induced by the peptide were detected. The major interaction was observed in the presence of the gel phase Lß, and was enhanced by a low cholesterol amount. With the appearance of the liquid ordered phase Lo, the effect was hindered. At high cholesterol content (20% mol), no detectable effects in the bilayer morphology or in its mechanical stability were recorded. These findings give new insights on the molecular mechanism of the amyloid/membrane interaction, highlighting the peculiar role of cholesterol.

Amyloid ß peptide conformational changes in the presence of a lipid membrane system.

Here we are presenting a comparative analysis of conformational changes of two amyloid ß peptides, Aß(25-35) and Aß(1-42), in the presence and absence of a phospholipid system, namely, POPC/POPS (1-palmitoyl-2-oleoylphospatidylcholine/palmitoyl-2-oleoylphospatidylserine), through Raman spectroscopy, synchrotron radiation micro Fourier-transform infrared spectroscopy, and micro X-ray diffraction. Ringlike samples were obtained from the evaporation of pure and mixed solutions of the proteins together with the POPC/POPS system on highly hydrophilic substrates. The results confirm the presence of a α-helical to ß-sheet transition from the internal rim of the ringlike samples to the external one in the pure Aß(25-35) residual, probably due to the convective flow inside the droplets sitting on highly hydrophilic substrates enhancing the local concentration of the peptide at the external edge of the dried drop. In contrast, the presence of POPC/POPS lipids in the peptide does not result in α-helical structures and introduces the presence of antiparallel ß-sheet material together with parallel ß-sheet structures and possible ß-turns. As a control, Aß(1-42) peptide was also tested and shows ß-sheet conformations independently from the presence of the lipid system. The µXRD analysis further confirmed these conclusions, showing how the absence of the phospholipid system induces in the Aß(25-35) a probable composite α/ß material while its coexistence with the peptide leads to a not oriented ß-sheet conformation. These results open interesting scenarios on the study of conformational changes of Aß peptides and could help, with further investigations, to better clarify the role of enzymes and alternative lipid systems involved in the amyloidosis process of Aß fragments.

Multifunctional substrates of thin porous alumina for cell biosensors.

We have fabricated anodic porous alumina from thin films (100/500 nm) of aluminium deposited on technological substrates of silicon/glass, and investigated the feasibility of this material as a surface for the development of analytical biosensors aiming to assess the status of living cells. To this goal, porous alumina surfaces with fixed pitch and variable pore size were analyzed for various functionalities. Gold coated (about 25 nm) alumina revealed surface enhanced Raman scattering increasing with the decrease in wall thickness, with factor up to values of approximately 10(4) with respect to the flat gold surface. Bare porous alumina was employed for micro-patterning and observation via fluorescence images of dye molecules, which demonstrated the surface capability for a drug-loading device. NIH-3T3 fibroblast cells were cultured in vitro and examined after 2 days since seeding, and no significant (P > 0.05) differences in their proliferation were observed on porous and non-porous materials. The effect on cell cultures of pore size in the range of 50-130 nm--with pore pitch of about 250 nm--showed no significant differences in cell viability and similar levels in all cases as on a control substrate. Future work will address combination of all above capabilities into a single device.

Stainless Steel Activation for Efficient Alkaline Oxygen Evolution in Advanced Electrolyzers.

Designing robust and cost-effective electrocatalysts for efficient alkaline oxygen evolution reaction (OER) is of great significance in the field of water electrolysis. In this study, an electrochemical strategy to activate stainless steel (SS) electrodes for efficient OER is introduced. By cycling the SS electrode within a potential window that encompasses the Fe(II)↔Fe(III) process, its OER activity can be enhanced to a great extent compared to using a potential window that excludes this redox reaction, decreasing the overpotential at current density of 100 mA cm-2 by 40 mV. Electrochemical characterization, Inductively Coupled Plasma - Optical Emission Spectroscopy, and operando Raman measurements demonstrate that the Fe leaching at the SS surface can be accelerated through a Fe → γ-Fe2O3 → Fe3O4 or FeO → Fe2+ (aq.) conversion process, leading to the sustained exposure of Cr and Ni species. While Cr leaching occurs during its oxidation process, Ni species display higher resistance to leaching and gradually accumulate on the SS surface in the form of OER-active Fe-incorporated NiOOH species. Furthermore, a potential-pulse strategy is also introduced to regenerate the OER-activity of 316-type SS for stable OER, both in the three-electrode configuration (without performance decay after 300 h at 350 mA cm-2) and in an alkaline water electrolyzer (≈30 mV cell voltage increase after accelerated stress test-AST). The AST-stabilized cell can still reach 1000 and 4000 mA cm-2 at cell voltages of 1.69 and 2.1 V, which makes it competitive with state-of-the-art electrolyzers based on ion-exchange membrane using Ir-based anodes.

Nanoscale structural and mechanical effects of beta-amyloid (1-42) on polymer cushioned membranes: a combined study by neutron reflectometry and AFM Force Spectroscopy.

The interaction of beta-amyloid peptides with lipid membranes is widely studied as trigger agents in Alzheimer's disease. Their mechanism of action at the molecular level is unknown and their interaction with the neural membrane is crucial to elucidate the onset of the disease. In this study we have investigated the interaction of water soluble forms of beta-amyloid Aß(1-42) with lipid bilayers supported by polymer cushion. A reproducible protocol for the preparation of a supported phospholipid membrane with composition mimicking the neural membrane and in physiological condition (PBS buffer, pH=7.4) was refined by neutron reflectivity. The change in structure and local mechanical properties of the membrane in the presence of Aß(1-42) was investigated by neutron reflectivity and Atomic Force Microscopy (AFM) Force Spectroscopy. Neutron reflectivity evidenced that Aß(1-42) interacts strongly with the supported membrane, causing a change in the scattering length density profile of the lipid bilayer, and penetrates into the membrane. Concomitantly, the local mechanical properties of the bilayer are deeply modified by the interaction with the peptide as seen by AFM Force Spectroscopy. These results may be of great importance for the onset of the Alzheimer's disease, since a simultaneous change in the structural and mechanical properties of the lipid matrix could influence all membrane based signal cascades.

α-Synuclein interacts differently with membranes mimicking the inner and outer leaflets of neuronal membranes.

The toxicity of α-synuclein (α-syn), the amyloidogenic protein responsible for Parkinson's disease, is likely related to its interaction with the asymmetric neuronal membrane. α-Syn exists as cytoplasmatic and as extracellular protein as well. To shed light on the different interactions occurring at the different α-syn localizations, we have here modelled the external and internal membrane leaflets of the neuronal membrane with two complex lipid mixtures, characterized by phase coexistence and with negative charge confined to either the ordered or the disordered phase, respectively. To this purpose, we selected a five-component (DOPC/SM/DOPE/DOPS/chol) and a four-component (DOPC/SM/GM1/chol) lipid mixtures, which contained the main membrane lipid constituents and exhibited a phase separation with formation of ordered domains. We have compared the action of α-syn in monomeric form and at different concentrations (1 nM, 40 nM, and 200 nM) with respect to lipid systems with different composition and shape by AFM, QCM-D, and vesicle leakage experiments. The experiments coherently showed a higher stability of the membranes composed by the internal leaflet mixture to the interaction with α-syn. Damage to membranes made of the external leaflet mixture was detected in a concentration-dependent manner. Interestingly, the membrane damage was related to the fluidity of the lipid domains and not to the presence of negatively charged lipids.

Alzheimer's disease amyloid-beta peptide analogue alters the ps-dynamics of phospholipid membranes.

We have investigated the influence of the neurotoxic Alzheimer's disease peptide amyloid-beta (25-35) on the dynamics of phospholipid membranes by means of quasi-elastic neutron scattering in the picosecond time-scale. Samples of pure phospholipids (DMPC/DMPS) and samples with amyloid-beta (25-35) peptide included have been compared. With two different orientations of the samples the directional dependence of the dynamics was probed. The sample temperature was varied between 290K and 320K to cover both the gel phase and the liquid-crystalline phase of the lipid membranes. The model for describing the dynamics combines a long-range translational diffusion of the lipid molecules and a spatially restricted diffusive motion. Amyloid-beta (25-35) peptide affects significantly the ps-dynamics of oriented lipid membranes in different ways. It accelerates the lateral diffusion especially in the liquid-crystalline phase. This is very important for all kinds of protein-protein interactions which are enabled and strongly influenced by the lateral diffusion such as signal and energy transducing cascades. Amyloid-beta (25-35) peptide also increases the local lipid mobility as probed by variations of the vibrational motions with a larger effect in the out-of-plane direction. Thus, the insertion of amyloid-beta (25-35) peptide changes not only the structure of phospholipid membranes as previously demonstrated by us employing neutron diffraction (disordering effect on the mosaicity of the lipid bilayer system) but also the dynamics inside the membranes. The amyloid-beta (25-35) peptide induced membrane alteration even at only 3mol% might be involved in the pathology of Alzheimer's disease as well as be a clue in early diagnosis and therapy.

Correlative nanoscopy: A multimodal approach to molecular resolution.

Atomic force microscopy (AFM) is a nano-mechanical tool uniquely suited for biological studies at the molecular scale. AFM operation is based on mechanical interaction between the tip and the sample, a mechanism of contrast capable of measuring different information, including surface topography, mechanical, and electrical properties. However, the lack of specificity highlights the need to integrate AFM data with other techniques providing compositional hints. In particular, optical microscopes based on fluorescence as a mechanism of contrast can access the local distribution of specific molecular species. The coupling between AFM and super-resolved fluorescence microscopy solves the resolution mismatch between AFM and conventional fluorescence optical microscopy. Recent advances showed that also the inherently label-free imaging capabilities of the AFM are fundamental to complement the fluorescence images. In this review, we have presented a brief historical view on correlative microscopy, and, finally, we have summarized the progress of correlative AFM-super-resolution microscopy in biological research.

Non-disruptive uptake of anionic and cationic gold nanoparticles in neutral zwitterionic membranes.

The potential toxicity of ligand-protected nanoparticles (NPs) on biological targets is crucial for their clinical translation. A number of studies are aimed at investigating the molecular mechanisms shaping the interactions between synthetic NPs and neutral plasma membranes. The role played by the NP surface charge is still widely debated. We compare, via liposome leakage assays, the perturbation induced by the penetration of sub-6 nm anionic and cationic Au NPs into model neutral lipid membranes composed of the zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Our charged Au NPs are functionalized by a mixture of the apolar 1-octanethiol and a ω-charged thiol which is either the anionic 11-mercapto-1-undecanesulfonate or the cationic (11-mercaptoundecyl)-N,N,N-trimethylammonium. In both cases, the NP uptake in the bilayer is confirmed by quartz crystal microbalance investigations. Our leakage assays show that both negatively and positively charged Au NPs do not induce significant membrane damage on POPC liposomes when penetrating into the bilayer. By means of molecular dynamics simulations, we show that the energy barrier for membrane penetration is the same for both NPs. These results suggest that the sign of the NP surface charge, per se, does not imply different physicochemical mechanisms of interaction with zwitterionic lipid membranes.

Cholesterol Hinders the Passive Uptake of Amphiphilic Nanoparticles into Fluid Lipid Membranes.

Plasma membranes represent pharmacokinetic barriers for the passive transport of site-specific drugs within cells. When engineered nanoparticles (NPs) are considered as transmembrane drug carriers, the plasma membrane composition can affect passive NP internalization in many ways. Among these, cholesterol-regulated membrane fluidity is probably one of the most biologically relevant. Herein, we consider small (2-5 nm in core diameter) amphiphilic gold NPs capable of spontaneously and nondisruptively entering the lipid bilayer of plasma membranes. We study their incorporation into model 1,2-dioleoyl-sn-glycero-3-phosphocholine membranes with increasing cholesterol content. We combine dissipative quartz crystal microbalance experiments, atomic force microscopy, and molecular dynamics simulations to show that membrane cholesterol, at biologically relevant concentrations, hinders the molecular mechanism for passive NP penetration within fluid bilayers, resulting in a dramatic reduction in the amount of NP incorporated.

Quantitative Super-Resolution Microscopy to Assess Adhesion of Neuronal Cells on Single-Layer Graphene Substrates.

Single Layer Graphene (SLG) has emerged as a critically important nanomaterial due to its unique optical and electrical properties and has become a potential candidate for biomedical applications, biosensors, and tissue engineering. Due to its intrinsic 2D nature, SLG is an ideal surface for the development of large-area biosensors and, due to its biocompatibility, can be easily exploited as a substrate for cell growth. The cellular response to SLG has been addressed in different studies with high cellular affinity for graphene often detected. Still, little is known about the molecular mechanism that drives/regulates the cellular adhesion and migration on SLG and SLG-coated interfaces with respect to other substrates. Within this scenario, we used quantitative super-resolution microscopy based on single-molecule localization to study the molecular distribution of adhesion proteins at the nanoscale level in cells growing on SLG and glass. In order to reveal the molecular mechanisms underlying the higher affinity of biological samples on SLG, we exploited stochastic optical reconstruction microscopy (STORM) imaging and cluster analysis, quantifying the super-resolution localization of the adhesion protein vinculin in neurons and clearly highlighting substrate-related correlations. Additionally, a comparison with an epithelial cell line (Chinese Hamster Ovary) revealed a cell dependent mechanism of interaction with SLG.

Chromatin Compaction Multiscale Modeling: A Complex Synergy Between Theory, Simulation, and Experiment.

Understanding the mechanisms that trigger chromatin compaction, its patterns, and the factors they depend on, is a fundamental and still open question in Biology. Chromatin compacts and reinforces DNA and is a stable but dynamic structure, to make DNA accessible to proteins. In recent years, computational advances have provided larger amounts of data and have made large-scale simulations more viable. Experimental techniques for the extraction and reconstitution of chromatin fibers have improved, reinvigorating theoretical and experimental interest in the topic and stimulating debate on points previously considered as certainties regarding chromatin. A great assortment of approaches has emerged, from all-atom single-nucleosome or oligonucleosome simulations to various degrees of coarse graining, to polymer models, to fractal-like structures and purely topological models. Different fiber-start patterns have been studied in theory and experiment, as well as different linker DNA lengths. DNA is a highly charged macromolecule, making ionic and electrostatic interactions extremely important for chromatin topology and dynamics. Indeed, the repercussions of varying ionic concentration have been extensively examined at the computational level, using all-atom, coarse-grained, and continuum techniques. The presence of high-curvature AT-rich segments in DNA can cause conformational variations, attesting to the fact that the role of DNA is both structural and electrostatic. There have been some tentative attempts to describe the force fields governing chromatin conformational changes and the energy landscapes of these transitions, but the intricacy of the system has hampered reaching a consensus. The study of chromatin conformations is an intrinsically multiscale topic, influenced by a wide range of biological and physical interactions, spanning from the atomic to the chromosome level. Therefore, powerful modeling techniques and carefully planned experiments are required for an overview of the most relevant phenomena and interactions. The topic provides fertile ground for interdisciplinary studies featuring a synergy between theoretical and experimental scientists from different fields and the cross-validation of respective results, with a multi-scale perspective. Here, we summarize some of the most representative approaches, and focus on the importance of electrostatics and solvation, often overlooked aspects of chromatin modeling.