Structure-based computational design of antibody mimetics: challenges and perspectives.

The design of antibody mimetics holds great promise for revolutionizing therapeutic interventions by offering alternatives to conventional antibody therapies. Structure-based computational approaches have emerged as indispensable tools in the rational design of those molecules, enabling the precise manipulation of their structural and functional properties. This review covers the main classes of designed antigen-binding motifs, as well as alternative strategies to develop tailored ones. We discuss the intricacies of different computational protein-protein interaction design strategies, showcased by selected successful cases in the literature. Subsequently, we explore the latest advancements in the computational techniques including the integration of machine and deep learning methodologies into the design framework, which has led to an augmented design pipeline. Finally, we verse onto the current challenges that stand in the way between high-throughput computer design of antibody mimetics and experimental realization, offering a forward-looking perspective into the field and the promises it holds to biotechnology.

C60-based Multivalent Glycoporphyrins Inhibit SARS-CoV-2 Specific Interaction with the DC-SIGN Transmembrane Receptor.

Since WHO has declared the COVID-19 outbreak a global pandemic, nearly seven million deaths have been reported. This efficient spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is facilitated by the ability of the spike glycoprotein to bind multiple cell membrane receptors. Although ACE2 is identified as the main receptor for SARS-CoV-2, other receptors could play a role in viral entry. Among others, C-type lectins such as DC-SIGN are identified as efficient trans-receptor for SARS-CoV-2 infection, so the use of glycomimetics to inhibit the infection through the DC-SIGN blockade is an encouraging approach. In this regard, multivalent nanostructures based on glycosylated [60]fullerenes linked to a central porphyrin scaffold have been designed and tested against DC-SIGN-mediated SARS-CoV-2 infection. First results show an outstanding inhibition of the trans-infection up to 90%. In addition, a deeper understanding of nanostructure-receptor binding is achieved through microscopy techniques, high-resolution NMR experiments, Quartz Crystal Microbalance experiments, and molecular dynamic simulations.

Parainfluenza Fusion Peptide Promotes Membrane Fusion by Assembling into Oligomeric Porelike Structures.

Paramyxoviruses are enveloped viruses harboring a negative-sense RNA genome that must enter the host's cells to replicate. In the case of the parainfluenza virus, the cell entry process starts with the recognition and attachment to target receptors, followed by proteolytic cleavage of the fusion glycoprotein (F) protein, exposing the fusion peptide (FP) region. The FP is responsible for binding to the target membrane, and it is believed to play a crucial role in the fusion process, but the mechanism by which the parainfluenza FP (PIFP) promotes membrane fusion is still unclear. To elucidate this matter, we performed biophysical experimentation of the PIFP in membranes, together with coarse grain (CG) and atomistic (AA) molecular dynamics (MD) simulations. The simulation results led to the pinpointing of the most important PIFP amino acid residues for membrane fusion and show that, at high concentrations, the peptide induces the formation of a water-permeable porelike structure. This structure promotes lipid head intrusion and lipid tail protrusion, which facilitates membrane fusion. Biophysical experimental results validate these findings, showing that, depending on the peptide/lipid ratio, the PIFP can promote fusion and/or membrane leakage. Our work furthers the understanding of the PIFP-induced membrane fusion process, which might help foster development in the field of viral entry inhibition.

Virus-inspired designs of antimicrobial nanocapsules.

Antimicrobial resistance is becoming a serious burden for drug design. The challenges are in finding novel approaches for effectively targeting a number of different bacterial strains, and in delivering these to the site of action. We propose here a novel approach that exploits the assembly of antimicrobial peptidic units in nanocapsules that can penetrate and rupture the bacterial membrane. Additionally, the chemical versatility of the designed units can be tailored to specific targets and to the delivery of genetic material in the cell. The proposed design exploits a ß-annulus (sequence ITHVGGVGGSIMAPVAVSRQLVGS) triskelion unit from the Tomato Bushy Stunt Virus, able to self assemble in solution, and functionalised with antimicrobial sequences to form dodecahedral antimicrobial nanocapsules. The stability and the activity of the antimicrobial ß-annulus capsule is measured by molecular dynamics simulations in water and in the presence of model membranes.

Nanocapsule designs for antimicrobial resistance.

The pressing need of new antimicrobial products is growing stronger, particularly because of widespread antimicrobial resistance, endangering our ability to treat common infections. The recent coronavirus pandemic has dramatically highlighted the necessity of effective antibacterial and antiviral protection. This work explores at the molecular level the mechanism of action of antibacterial nanocapsules assembled in virus-like particles, their stability and their interaction with mammal and antimicrobial model membranes. We use Molecular Dynamics with force-fields of different granularity and protein design strategies to study the stability, self-assembly and membrane poration properties of these nanocapsules.

Evidence of Band-Edge Hole Levels Inversion in Spherical CuInS2 Quantum Dots.

CuInS2 (CIS) quantum dots (QDs) have emerged as one of the most promising candidates for application in a number of new technologies, mostly due to their heavy-metal-free composition and their unique optical properties. Among those, the large Stokes shift and the long-lived excited state are the most striking ones. Although these properties are important, the physical mechanism that originates them is still under debate. Here, we use two-photon absorption spectroscopy and ultrafast dynamics studies to investigate the physical origin of those phenomena. From the two-photon absorption spectroscopy, we observe yet another unique property of CIS QDs, a two-photon absorption transition below the one-photon absorption band edge, which has never been observed before for any other semiconductor nanostructure. This originates from the inversion of the 1S and 1P hole level order at the top of the valence band and results in a blue-shift of the experimentally measured one photon absorption edge by nearly 100 to 200 meV. However, this shift is not large enough to account for the Stokes shift observed, 200-500 meV. Consequently, despite the existence of the below band gap optical transition, photoluminescence in CIS QDs must originate from trap sites. These conclusions are reinforced by the multiexciton dynamics studies. From those, we demonstrate that biexciton Auger recombination behaves similarly to negative trion dynamics on these nanomaterials, which suggests that the trap state is an electron donating site.

Two-Photon Absorption and Two-Photon-Induced Gain in Perovskite Quantum Dots.

Perovskite quantum dots (PQDs) emerged as a promising class of material for applications in lighting devices, including light emitting diodes and lasers. In this work, we explore nonlinear absorption properties of PQDs showing the spectral signatures and the size dependence of their two-photon absorption (2PA) cross-section, which can reach values higher than 106 GM. The large 2PA cross section allows for low threshold two-photon induced amplified spontaneous emission (ASE), which can be as low as 1.6 mJ/cm2. We also show that the ASE properties are strongly dependent on the nanomaterial size, and that the ASE threshold, in terms of the average number of excitons, decreases for smaller PQDs. Investigating the PQDs biexciton binding energy, we observe strong correlation between the increasing on the biexciton binding energy and the decreasing on the ASE threshold, suggesting that ASE in PQDs is a biexciton-assisted process.

Two-photon absorption in a series of 2,6-disubstituted BODIPY dyes.

We report on the two-photon absorption spectra of a series of 2,6-disubstituted BODIPY dyes. Depending on the substituents, we observe increasing two-photon absorption cross sections with values up to 350 GM compared to 70 GM in the unsubstituted dye. Quantum chemical calculations are performed to assign the absorption bands and to understand the factors controlling the size of the two-photon absorption cross section. Both the maximum of the two-photon absorption band as well as the red-shift of the whole spectrum correlate with the ability of the substituents to extend the π-electron system of the dye. The above-mentioned intense two-photon absorption band corresponds to the absorption of photons with 1.3 eV, which is at the first near-infrared transparency window for biological tissues. The dyes could thus be suitable for bio-imaging applications.

Amino acid polymorphisms in the fibronectin-binding repeats of fibronectin-binding protein A affect bond strength and fibronectin conformation.

The Staphylococcus aureus cell surface contains cell wall-anchored proteins such as fibronectin-binding protein A (FnBPA) that bind to host ligands (e.g. fibronectin; Fn) present in the extracellular matrix of tissue or coatings on cardiac implants. Recent clinical studies have found a correlation between cardiovascular infections caused by S. aureus and nonsynonymous SNPs in FnBPA. Atomic force microscopy (AFM), surface plasmon resonance (SPR), and molecular simulations were used to investigate interactions between Fn and each of eight 20-mer peptide variants containing amino acids Ala, Asn, Gln, His, Ile, and Lys at positions equivalent to 782 and/or 786 in Fn-binding repeat-9 of FnBPA. Experimentally measured bond lifetimes (1/koff) and dissociation constants (Kd = koff/kon), determined by mechanically dissociating the Fn·peptide complex at loading rates relevant to the cardiovascular system, varied from the lowest-affinity H782A/K786A peptide (0.011 s, 747 µm) to the highest-affinity H782Q/K786N peptide (0.192 s, 15.7 µm). These atomic force microscopy results tracked remarkably well to metadynamics simulations in which peptide detachment was defined solely by the free-energy landscape. Simulations and SPR experiments suggested that an Fn conformational change may enhance the stability of the binding complex for peptides with K786I or H782Q/K786I (Kdapp = 0.2-0.5 µm, as determined by SPR) compared with the lowest-affinity double-alanine peptide (Kdapp = 3.8 µm). Together, these findings demonstrate that amino acid substitutions in Fn-binding repeat-9 can significantly affect bond strength and influence the conformation of Fn upon binding. They provide a mechanistic explanation for the observation of nonsynonymous SNPs in fnbA among clinical isolates of S. aureus that cause endovascular infections.

Structure-based design, synthesis and antitumoral evaluation of enulosides.

Enulosides, carbohydrate derivatives containing an α,ß-unsaturated carbonyl unit, were designed and obtained in high yields and isomeric purity. All synthesized compounds exhibited antitumoral activity in micromolar range against four tested tumor cells lines, being the best results observed for HL-60 cells. These compounds open new possibilities to prepare an array of more active, site-specific or selective antitumor agents. 2016 Elsevier Ltd. All rights reserved.

Efficient Biexciton Interaction in Perovskite Quantum Dots Under Weak and Strong Confinement.

Cesium lead halide perovskite quantum dots (PQDs) have emerged as a promising new platform for lighting applications. However, to date, light emitting diodes (LED) based on these materials exhibit limited efficiencies. One hypothesized limiting factor is fast nonradiative multiexciton Auger recombination. Using ultrafast spectroscopic techniques, we investigate multicarrier interaction and recombination mechanisms in cesium lead halide PQDs. By mapping the dependence of the biexciton Auger lifetime and the biexciton binding energy on nanomaterial size and composition, we find unusually strong Coulomb interactions among multiexcitons in PQDs. This results in weakly emissive biexcitons and trions, and accounts for low light emission efficiencies. We observe that, for strong confinement, the biexciton lifetime depends linearly on the PQD volume. This dependence becomes sublinear in the weak confinement regime as the PQD size increases beyond the Bohr radius. We demonstrate that Auger recombination is faster in PQDs compared to CdSe nanoparticles having the same volume, suggesting a stronger Coulombic interaction in the PQDs. We confirm this by demonstrating an increased biexciton binding energy, which reaches a maximum of about 100 meV, fully three times larger than in CdSe quantum dots. The biexciton shift can lead to low-threshold optical gain in these materials. These findings also suggest that materials engineering to reduce Coulombic interaction in cesium lead halide PQDs could improve prospects for high efficiency optoelectronic devices. Core-shell structures, in particular type-II nanostructures, which are known to reduce the bandedge Coulomb interaction in CdSe/CdS, could beneficially be applied to PQDs with the goal of increasing their potential in lighting applications.

Bioenergy and African transformation.

Among the world's continents, Africa has the highest incidence of food insecurity and poverty and the highest rates of population growth. Yet Africa also has the most arable land, the lowest crop yields, and by far the most plentiful land resources relative to energy demand. It is thus of interest to examine the potential of expanded modern bioenergy production in Africa. Here we consider bioenergy as an enabler for development, and provide an overview of modern bioenergy technologies with a comment on application in an Africa context. Experience with bioenergy in Africa offers evidence of social benefits and also some important lessons. In Brazil, social development, agricultural development and food security, and bioenergy development have been synergistic rather than antagonistic. Realizing similar success in African countries will require clear vision, good governance, and adaptation of technologies, knowledge, and business models to myriad local circumstances. Strategies for integrated production of food crops, livestock, and bioenergy are potentially attractive and offer an alternative to an agricultural model featuring specialized land use. If done thoughtfully, there is considerable evidence that food security and economic development in Africa can be addressed more effectively with modern bioenergy than without it. Modern bioenergy can be an agent of African transformation, with potential social benefits accruing to multiple sectors and extending well beyond energy supply per se. Potential negative impacts also cut across sectors. Thus, institutionally inclusive multi-sector legislative structures will be more effective at maximizing the social benefits of bioenergy compared to institutionally exclusive, single-sector structures.

QM/MM simulations of amyloid-ß 42 degradation by IDE in the presence and absence of ATP.

The ability of the insulin-degrading enzyme (IDE) to degrade amyloid-ß 42 (Aß42), a process regulated by ATP, has been studied as an alternative path in the development of drugs against Alzheimer's disease. In this study, we calculated the potential of mean force for the degradation of Aß42 by IDE in the presence and absence of ATP by umbrella sampling with hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, using the SCC-DFTB QM Hamiltonian and Amber ff99SB force field. Results indicate that the reaction occurs in two steps: The first step is characterized by the formation of the intermediate. The second step is characterized by breaking the peptide bond of the substrate, the latter being the rate-determining step. In our simulations, the activation energy barrier in the absence of ATP is 15 ± 2 kcal mol(-1), which is 7 kcal mol(-1) lower than in the presence of ATP, indicating that the presence of the nucleotide decreases the reaction rate by about 10(5) times.

Molecular dynamics simulations reveal a novel mechanism for ATP inhibition of insulin degrading enzyme.

Regulation of brain levels of the Amyloid-ß 42 (Aß42) polypeptide by IDE has recently been linked with possible routes for new therapies against Alzheimer's disease (AD). One important aspect is the regulatory mechanism of IDE by ATP, which is an IDE activator in degrading small peptides and an inhibitor in degrading larger peptides, such as Aß42. This relationship was investigated in this study. We present molecular dynamics simulations of Aß42 complexed with IDE, in the absence or presence of either ATP or excess Na(+) and Cl(-) ions. Results suggest a previously unreported inhibition mechanism that depends on charge-induced structural modifications in the active site and interactions simultaneously involving ATP, Aß42, and IDE. Such interactions exist only when both ATP and Aß42 are simultaneously present in the catalytic chamber. This mechanism results in allosteric, noncompetitive inhibition with apparent decrease of substrate affinity, in accordance with experiment.

Synthesis and evaluation of (-)-Massoialactone and analogues as potential anticancer and anti-inflammatory agents.

(-)-Massoialactone, an α,ß-unsaturated δ-lactone isolated from Cryptocarya massoia, and five analogues were synthesized and their antiproliferative and anti-inflammatory activities were evaluated. The lactones were able to mimic the "core" functional group required for the biological activity of their parent natural compounds suggesting that substantially altered analogues may retain their properties.

Liquid-core, liquid-cladding photonic crystal fibers.

We experimentally demonstrate a simple and novel technique to simultaneously insert a liquid into the core of a hollow-core photonic crystal fiber (PCF) and a different liquid into its cladding. The result is a liquid-core, liquid-cladding waveguide in which the two liquids can be selected to yield specific guidance characteristics. As an example, we tuned the core-cladding index difference by proper choice of the inserted liquids to obtain control over the number of guided modes. Single-mode guidance was achieved for a particular choice of liquids. We also experimentally and theoretically investigated the nature of light confinement and observed the transition from photonic bandgap to total internal reflection guidance both with the core-cladding index contrast and with the PCF length.