Not so rigid capsids based on cyclodextrin complexes: Keys to design.

HYPOTHESIS: Membranes based on cyclodextrin complexes can be used as functional nanocarrier envelopers by chemical modifications of the cyclodextrin hydroxyl groups or by encapsulating different ligands in their cavities. EXPERIMENTS: Molecular dynamics simulations of monolayers and bilayers based on supramolecular complexes consisting of two α or ß-cyclodextrin and one sodium dodecylsulfate or dodecane at 283 K and at 298 K were performed. FINDINGS: It is shown that the structure and main interactions stabilizing the membranes, as well as their permeability to water and ions can be tuned by changing the cyclodextrin, the ligand, the number of layers or/and the temperature. These results provide new evidences about both their dynamic nature and the interactions responsible for the stabilization of the membranes and will facilitate the design of new functional capsides and applications based on cyclodextrin complexes.

Molecular Dynamics Simulations of Transmembrane Cyclic Peptide Nanotubes Using Classical Force Fields, Hydrogen Mass Repartitioning, and Hydrogen Isotope Exchange Methods: A Critical Comparison.

Self-assembled cyclic peptide nanotubes with alternating D- and L-amino acid residues in the sequence of each subunit have attracted a great deal of attention due to their potential for new nanotechnology and biomedical applications, mainly in the field of antimicrobial peptides. Molecular dynamics simulations can be used to characterize these systems with atomic resolution at different time scales, providing information that is difficult to obtain via wet lab experiments. However, the performance of classical force fields typically employed in the simulation of biomolecules has not yet been extensively tested with this kind of highly constrained peptide. Four different classical force fields (AMBER, CHARMM, OPLS, and GROMOS), using a nanotube formed by eight D,L-α-cyclic peptides inserted into a lipid bilayer as a model system, were employed here to fill this gap. Significant differences in the pseudo-cylindrical cavities formed by the nanotubes were observed, the most important being the diameter of the nanopores, the number and location of confined water molecules, and the density distribution of the solvent molecules. Furthermore, several modifications were performed on GROMOS54a7, aiming to explore acceleration strategies of the MD simulations. The hydrogen mass repartitioning (HMR) and hydrogen isotope exchange (HIE) methods were tested to slow down the fastest degrees of freedom. These approaches allowed a significant increase in the time step employed in the equation of the motion integration algorithm, from 2 fs up to 5-7 fs, with no serious changes in the structural and dynamical properties of the nanopores. Subtle differences with respect to the simulations with the unmodified force fields were observed in the concerted movements of the cyclic peptides, as well as in the lifetime of several H-bonds. All together, these results are expected to contribute to better understanding of the behavior of self-assembled cyclic peptide nanotubes, as well as to support the methods tested to speed up general MD simulations; additionally, they do provide a number of quantitative descriptors that are expected to be used as a reference to design new experiments intended to validate and complement computational studies of antimicrobial cyclic peptides.

Unsupervised bubble calorimetry analysis: Surface tension from isothermal titration calorimetry.

HYPOTHESIS: The injection of air into the sample cell of an isothermal titration calorimeter containing a liquid provides a rich-in-information signal, with a periodic contribution arising from the creation, growing and release of bubbles. The identification and analysis of such contributions allow the accurate determination of the surface tension of the target liquid. EXPERIMENTS: Air is introduced at a constant rate into the sample cell of the calorimeter containing either a pure liquid or a solution. The resulting calorimetric signal is analyzed by a new algorithm, which is implemented into a computational code. FINDINGS: The thermal power generated by our experiments is often noisy, thus hiding the periodic signal arising from the bubbles' formation and release. The new algorithm was tested with a range of different types of calorimetric raw data, some of them apparently being just noise. In all cases, the contribution of the bubbles to the signal was isolated and the corresponding period was successfully determined in an automated way. It is also shown that two reference measurements suffice to calibrate the instrument at a given temperature, regardless the injection rate, allowing the direct determination of surface tension values for the liquid contained in the sample cell.

Differential Entropy: An Appropriate Analysis to Interpret the Shape Complexity of Self-Similar Organic Islands.

Differential entropy, along with fractal dimension, is herein employed to describe and interpret the shape complexity of self-similar organic islands. The islands are imaged with in situ Atomic Force Microscopy, following, step-by-step, the evolution of their shape while deposition proceeds. The fractal dimension shows a linear correlation with the film thickness, whereas the differential entropy presents an exponential plateau. Plotting differential entropy versus fractal dimension, a linear correlation can be found. This analysis enables one to discern the 6T growth on different surfaces, i.e., native SiOx or 6T layer, and suggests a more comprehensive interpretation of the shape evolution. Changes in fractal dimension reflect rougher variations of the island contour, whereas changes in differential entropy correlates with finer contour details. The computation of differential entropy therefore helps to obtain more physical information on the island shape dependence on the substrate, beyond the standard description obtained with the fractal dimension.

Transmembrane Self-Assembled Cyclic Peptide Nanotubes Based on α-Residues and Cyclic δ-Amino Acids: A Computational Study.

Self-assembling cyclic peptide nanotubes have been shown to function as synthetic, integral transmembrane channels. The combination of natural and nonnatural aminoacids in the sequence of cyclic peptides enables the control not only of their outer surface but also of the inner cavity behavior and properties, affecting, for instance, their permeability to different molecules including water and ions. Here, a thorough computational study on a new class of self-assembling peptide motifs, in which δ-aminocycloalkanecarboxylic acids are alternated with natural α-amino acids, is presented. The presence of synthetic δ-residues creates hydrophobic regions in these α,δ-SCPNs, which makes them especially attractive for their potential implementation in the design of new drug or diagnostic agent carrier systems. Using molecular dynamics simulations, the behavior of water molecules, different ions (Li+, Na+, K+, Cs+, and Ca2+), and their correspondent counter Cl- anions is extensively investigated in the nanoconfined environment. The structure and dynamics are mutually combined in a diving immersion inside these transmembrane channels to discover a fascinating submarine nanoworld where star-shaped water channels guide the passage of cations and anions therethrough.

Fluid interface calorimetry.

HYPOTHESIS: Amphiphilic molecules spontaneously adsorb to fluid polar-nonpolar interfaces. The timescale of such adsorption depends on the molecular size and structure of the solute. This process should be accompanied by a power heat exchange that could be detected by commercial isothermal calorimeters. EXPERIMENTS: Air is injected in the bulk of different aqueous solutions contained in the sample cell of an isothermal titration calorimeter. The formation of the resulting bubbles leads to a liquid/air interface to which the solute molecules spontaneously adsorb. Continuous injection experiments to produce multiple bubbles as well as experiments with static bubbles stand from the capillary tip, aiming to observe slow adsorption processes, were performed. FINDINGS: The power associated with the formation, growth and release of air bubbles in different liquids was measured. Different independent contributions that can be associated to the pressure change in the gas phase, the evaporation-condensation of the solvent, the increase of interfacial area, the change in the heat capacity of the sample cell content, and the release of the bubble were observed. The periodic pattern produced by the continuous injection of air at a constant rate is used to determine the surface tension of different liquids, including solutions of different molecules and (bio)macromolecules.

The Lord of the NanoRings: Cyclodextrins and the battle against SARS-CoV-2.

A handful of singular structures and laws can be observed in nature. They are not always evident but, once discovered, it seems obvious how to take advantage of them. In chemistry, the discovery of reproducible patterns stimulates the imagination to develop new functional materials and technological or medical applications. Two clear examples are helical structures at different levels in biological polymers as well as ring and spherical structures of different size and composition. Rings are intuitively observed as holes able to thread elongated structures. A large number of real and fictional stories have rings as inanimate protagonists. The design, development or just discovering of a special ring has often been taken as a symbol of power or success. Several examples are the Piscatory Ring wore by the Pope of the Catholic Church, the NBA Championship ring and the One Ring created by the Dark Lord Sauron in the epic story The Lord of the Rings. In this work, we reveal the power of another extremely powerful kind of rings to fight against the pandemic which is currently affecting the whole world. These rings are as small as ~1 nm of diameter and so versatile that they are able to participate in the attack of viruses, and specifically SARS-CoV-2, in a large range of different ways. This includes the encapsulation and transport of specific drugs, as adjuvants to stabilize proteins, vaccines or other molecules involved in the infection, as cholesterol trappers to destabilize the virus envelope, as carriers for RNA therapies, as direct antiviral drugs and even to rescue blood coagulation upon heparin treatment. "One ring to rule them all. One ring to find them. One ring to bring them all and in the darkness bind them." J. R. R. Tolkien.

AFFINImeter: A software to analyze molecular recognition processes from experimental data.

The comprehension of molecular recognition phenomena demands the understanding of the energetic and kinetic processes involved. General equations valid for the thermodynamic analysis of any observable that is assessed as a function of the concentration of the involved compounds are described, together with their implementation in the AFFINImeter software. Here, a maximum of three different molecular species that can interact with each other to form an enormous variety of supramolecular complexes are considered. The corrections currently employed to take into account the effects of dilution, volume displacement, concentration errors and those due to external factors, especially in the case of ITC measurements, are included. The methods used to fit the model parameters to the experimental data, and to generate the uncertainties are described in detail. A simulation tool and the so called kinITC analysis to get kinetic information from calorimetric experiments are also presented. An example of how to take advantage of the AFFINImeter software for the global multi-temperature analysis of a system exhibiting cooperative 1:2 interactions is presented and the results are compared with data previously published. Some useful recommendations for the analysis of experiments aimed at studying molecular interactions are provided.

STAND: Surface Tension for Aggregation Number Determination.

Taking advantage of the extremely high dependence of surface tension on the concentration of amphiphilic molecules in aqueous solution, a new model based on the double equilibrium between free and aggregated molecules in the liquid phase and between free molecules in the liquid phase and those adsorbed at the air/liquid interface is presented and validated using literature data and fluorescence measurements. A key point of the model is the use of both the Langmuir isotherm and the Gibbs adsorption equation in terms of free molecules instead of the nominal concentration of the solute. The application of the model should be limited to non ionic compounds since it does not consider the presence of counterions. It requires several coupled nonlinear fittings for which we developed a software that is publicly available in our server as a web application. Using this tool, it is straightforward to get the average aggregation number of an amphiphile, the micellization free energy, the adsorption constant, the maximum surface excess (and so the minimum area per molecule), the distribution of solute in the liquid phase between free and aggregate species, and the surface coverage in only a couple of seconds, just by uploading a text file with surface tension vs concentration data and the corresponding uncertainties.