Orientational Pathways during Protein Translocation through Polymer-Modified Nanopores.

Protein translocation through nanopores holds significant promise for applications in biotechnology, biomolecular analysis, and medicine. However, the interpretation of signals generated by the translocation of the protein remains challenging. In this way, it is crucial to gain a comprehensive understanding on how macromolecules translocate through a nanopore and to identify what are the critical parameters that govern the process. In this study, we investigate the interplay between protein charge regulation, orientation, and nanopore surface modifications using a theoretical framework that allows us to explicitly take into account the acid-base reactions of the titrable amino acids in the proteins and in the polyelectrolytes grafted to the nanopore surface. Our goal is to thoroughly characterize the translocation process of different proteins (GFP, ß-lactoglobulin, lysozyme, and RNase) through nanopores modified with weak polyacids. Our calculations show that the charge regulation mechanism exerts a profound effect on the translocation process. The pH-dependent interactions between proteins and charged polymers within the nanopore lead to diverse free energy landscapes with barriers, wells, and flat regions dictating translocation efficiency. Comparison of different proteins allows us to identify the significance of protein isoelectric point, size, and morphology in the translocation behavior. Taking advantage of these insights, we propose pH-responsive nanopores that can load proteins at one pH and release them at another, offering opportunities for controlled protein delivery, separation, and sensing applications.

Molecular Theory: A Tool for Predicting the Outcome of Self-Assembly of Polymers, Nanoparticles, Amphiphiles, and Other Soft Materials.

The supramolecular organization of soft materials, such as colloids, polymers, and amphiphiles, results from a subtle balance of weak intermolecular interactions and entropic forces. This competition can drive the self-organization of soft materials at the nano-/mesoscale. Modeling soft-matter self-assembly requires, therefore, considering a complex interplay of forces at the relevant length scales without sacrificing the molecular details that define the chemical identity of the system. This mini-review focuses on the application of a tool known as molecular theory to study self-assembly in different types of soft materials. This tool is based on extremizing an approximate free energy functional of the system, and, therefore, it provides a direct, computationally affordable estimation of the stability of different self-assembled morphologies. Moreover, the molecular theory explicitly incorporates structural details of the chemical species in the system, accounts for their conformational degrees of freedom, and explicitly includes their chemical equilibria. This mini-review introduces the general ideas behind the theoretical formalism and discusses its advantages and limitations compared with other theoretical tools commonly used to study self-assembled soft materials. Recent application examples are discussed: the self-patterning of polyelectrolyte brushes on planar and curved surfaces, the formation of nanoparticle (NP) superlattices, and the self-organization of amphiphiles into micelles of different shapes. Finally, prospective methodological improvements and extensions (also relevant for related theoretical tools) are analyzed.

Proteins Adsorbing onto Surface-Modified Nanoparticles: Effect of Surface Curvature, pH, and the Interplay of Polymers and Proteins Acid-Base Equilibrium.

Protein adsorption onto nanomaterials is a process of vital significance and it is commonly controlled by functionalizing their surface with polymers. The efficiency of this strategy depends on the design parameters of the nanoconstruct. Although significant amount of work has been carried out on planar surfaces modified with different types of polymers, studies investigating the role of surface curvature are not as abundant. Here, we present a comprehensive and systematic study of the protein adsorption process, analyzing the effect of curvature and morphology, the grafting of polymer mixtures, the type of monomer (neutral, acidic, basic), the proteins in solution, and the conditions of the solution. The theoretical approach we employed is based on a molecular theory that allows to explicitly consider the acid-base reactions of the amino acids in the proteins and the monomers on the surface. The calculations showed that surface curvature modulates the molecular organization in space, but key variables are the bulk pH and salt concentration (in the millimolar range). When grafting the NP with acidic or basic polymers, the surface coating could disfavor or promote adsorption, depending on the solution's conditions. When NPs are in contact with protein mixtures in solution, a nontrivial competitive adsorption process is observed. The calculations reflect the balance between molecular organization and chemical state of polymers and proteins, and how it is modulated by the curvature of the underlying surface.

Theoretical Modeling of Chemical Equilibrium in Weak Polyelectrolyte Layers on Curved Nanosystems.

Surface functionalization with end-tethered weak polyelectrolytes (PE) is a versatile way to modify and control surface properties, given their ability to alter their degree of charge depending on external cues like pH and salt concentration. Weak PEs find usage in a wide range of applications, from colloidal stabilization, lubrication, adhesion, wetting to biomedical applications such as drug delivery and theranostics applications. They are also ubiquitous in many biological systems. Here, we present an overview of some of the main theoretical methods that we consider key in the field of weak PE at interfaces. Several applications involving engineered nanoparticles, synthetic and biological nanopores, as well as biological macromolecules are discussed to illustrate the salient features of systems involving weak PE near an interface or under (nano)confinement. The key feature is that by confining weak PEs near an interface the degree of charge is different from what would be expected in solution. This is the result of the strong coupling between structural organization of weak PE and its chemical state. The responsiveness of engineered and biological nanomaterials comprising weak PE combined with an adequate level of modeling can provide the keys to a rational design of smart nanosystems.

Insights into the Role of Counterions on Polyelectrolyte-Modified Nanopore Accessibility.

Nanopores play a decisive role in different technologies from oil production, separation, and sensing to drug delivery or catalysis and energy conversion. In recent years, abilities to functionalize nanopores have advanced significantly. Thereby, nanopores functionalized with polyelectrolytes or responsive polymers show fascinating transport properties, such as gated or gradually controlled ionic permselectivity. Nonetheless, understanding the influence of external parameters such as ion type or concentration on nanopore performance, and thus on the mentioned applications, remains a challenge but is crucial for applications. In this work, the effect of different counterions on the wetting and ionic transport in poly(2-(methacryloyloxy)ethyltrimethylammonium chloride)-functionalized silica mesopores (pore diameter <10 nm) was experimentally and theoretically investigated. Static contact angles covered a range from 45 to almost 90° by exclusively changing the counterion. Ionic pore accessibility was also strongly dependent on the counterion present and was found to gradually change from accessible pores up to complete, pH-independent ion exclusion. On the basis of molecular theory calculations, these experimental observations were rationalized on the basis of ion binding between the [2-(methacryloyloxy)ethyl]trimethylammonium chloride monomers and the counterions. In addition, the theoretical framework provided a nanoscopic view into the molecular organization inside the pores, showing a strong dependence of ion concentration and ion distribution profiles along the pore radius in dependence of the present ions. The obtained insights on the role of counterion type and ion binding in nanopores are expected to have direct impact on the above-mentioned applications.

The interplay of nanointerface curvature and calcium binding in weak polyelectrolyte-coated nanoparticles.

When engineering nanomaterials for application in biological systems, it is important to understand how multivalent ions, such as calcium, affect the structural and chemical properties of polymer-modified nanoconstructs. In this work, a recently developed molecular theory was employed to study the effect of surface curvature on the calcium-induced collapse of end-tethered weak polyelectrolytes. In particular, we focused on cylindrical and spherical nanoparticles coated with poly(acrylic acid) in the presence of different amounts of Ca2+ ions. We describe the structural changes that grafted polyelectrolytes undergo as a function of calcium concentration, surface curvature, and morphology. The polymer layers collapse in aqueous solutions that contain sufficient amounts of Ca2+ ions. This collapse, due to the formation of calcium bridges, is not only controlled by the calcium ion concentration but also strongly influenced by the curvature of the tethering surface. The transition from a swollen to a collapsed layer as a function of calcium concentration broadens and shifts to lower amounts of calcium ions as a function of the radius of cylindrical and spherical nanoparticles. The results show how the interplay between calcium binding and surface curvature governs the structural and functional properties of the polymer molecules. This would directly impact the fate of weak polyelectrolyte-coated nanoparticles in biological environments, in which calcium levels are tightly regulated. Understanding such interplay would also contribute to the rational design and optimization of smart interfaces with applications in, e.g., salt-sensitive and ion-responsive materials and devices.

What is the role of curvature on the properties of nanomaterials for biomedical applications?

The use of nanomaterials for drug delivery and theranostics applications is a promising paradigm in nanomedicine, as it brings together the best features of nanotechnolgy, molecular biology, and medicine. To fully exploit the synergistic potential of such interdisciplinary strategy, a comprehensive description of the interactions at the interface between nanomaterials and biological systems is not only crucial, but also mandatory. Routine strategies to engineer nanomaterial-based drugs comprise modifying their surface with biocompatible and targeting ligands, in many cases resorting to modular approaches that assume additive behavior. However, emergent behavior can be observed when combining confinement and curvature. The final properties of functionalized nanomaterials become dependent not only on the properties of their constituents but also on the geometry of the nano-bio interface, and on the local molecular environment. Modularity no longer holds, and the coupling between interactions, chemical equilibrium, and molecular organization has to be directly addressed in order to design smart nanomaterials with controlled spatial functionalization envisioning optimized biomedical applications. Nanoparticle's curvature becomes an integral part of the design strategy, enabling to control and engineer the chemical and surface properties with molecular precision. Understanding how nanoparticle size, morphology, and surface chemistry are interrelated will put us one step closer to engineering nanobiomaterials capable of mimicking biological structures and their behaviors, paving the way into applications and the possibility to elucidate the use of curvature by biological systems. WIREs Nanomed Nanobiotechnol 2016, 8:334-354. doi: 10.1002/wnan.1365 For further resources related to this article, please visit the WIREs website.

The role of steric interactions in dispersion of carbon nanotubes by poly(3-alkyl thiophenes) in organic solvents.

The dispersion mechanism of carbon nanotubes (CNTs) in organic solutions of poly(3-alkyl thiophenes, P3ATs) was examined in a study that combines experimental investigation of the dispersion mechanism and molecular theory calculations of the effective intertube potential for polymer wrapped CNTs. The minimal polymer concentration required for dispersion of CNT served as a comparative measure of the efficiency of P3AT derivatives that differ in the length of the alkyl side chains or the regiochemistry of the monomers in three solvents: 1,2 and 1,3 dichlorobenzene and chloroform. While previous studies focused on the adsorption mechanism of P3ATs onto SWNT, we find that the dispersing efficiency depends not only on the stacking of the polymer backbone onto the CNT ("wrapping"), but also on the steric repulsion among the side chains of adsorbed P3ATs. In accordance with the experiments, our calculations indicate that high surface density of polymers with longer side chains and large tube diameter promote the formation of stable dispersions of relatively high loadings of CNTs, at low polymer:CNT ratios.

Tetrachlorocarbonyliridates: water-soluble carbon monoxide releasing molecules rate-modulated by the sixth ligand.

A new family of compounds is presented as potential carbon monoxide releasing molecules (CORMs). These compounds, based on tetrachlorocarbonyliridate(III) derivatives, were synthesized and fully characterized by X-ray diffraction, electrospray mass spectrometry, IR, NMR, and density functional theory calculations. The rate of CO release was studied via the myoglobin assay. The results showed that the rate depends on the nature of the sixth ligand, trans to CO, and that a significant modulation on the release rate can be produced by changing the ligand. The reported compounds are soluble in aqueous media, and the rates of CO release are comparable with those for known CORMs, releasing CO at a rate of 0.03-0.58 µM min(-1) in a 10 µM solution of myoglobin and 10 µM of the complexes.