Computational Design of Peptide Assemblies.

With the ongoing development of peptide self-assembling materials, there is growing interest in exploring novel functional peptide sequences. From short peptides to long polypeptides, as the functionality increases, the sequence space is also expanding exponentially. Consequently, attempting to explore all functional sequences comprehensively through experience and experiments alone has become impractical. By utilizing computational methods, especially artificial intelligence enhanced molecular dynamics (MD) simulation and de novo peptide design, there has been a significant expansion in the exploration of sequence space. Through these methods, a variety of supramolecular functional materials, including fibers, two-dimensional arrays, nanocages, etc., have been designed by meticulously controlling the inter- and intramolecular interactions. In this review, we first provide a brief overview of the current main computational methods and then focus on the computational design methods for various self-assembled peptide materials. Additionally, we introduce some representative protein self-assemblies to offer guidance for the design of self-assembling peptides.

Enzyme-Driven, Switchable Catalysis Based on Dynamic Self-Assembly of Peptides.

Covalent regulatory systems of enzymes are widely used to modulate biological enzyme activities. Inspired by the regulation of reactive-site phosphorylation in organisms, we developed peptide-based catecholase mimetics with switchable catalytic activity and high selectivity through the co-assembly of nanofibers comprising peptides and copper ions (Cu2+ ). Through careful design and modification of the peptide backbone structure based on the change in the free energy of the system, we identified the peptide with the most effective reversible catalytic activity. Kinase/phosphatase switches were used to control the reversible transition of nanofiber formation and depolymerization, as well as to modulate the active-site microenvironment. Notably, the self-assembly and disassembly processes of nanofibers were simulated using coarse-grained molecular dynamics. Furthermore, theoretical calculations confirmed the coordination of the peptide and Cu2+ , forming a zipper-like four-ligand structure at the catalytically active center of the nanofibers. Additionally, we conducted a comprehensive analysis of the catalytic mechanism. This study opens novel avenues for designing biomimetic enzymes with ordered structures and dynamic catalytic activities.

Topical Drug Delivery of Concentrated Cabazitaxel in an α-Tocopherol and DMSO Solution.

Topical chemotherapy approaches are relevant for certain skin cancer treatments. This study observes that cabazitaxel (CTX), a broad-spectrum second-generation taxane cytotoxic agent, can be dissolved in α-tocopherol at high concentrations exceeding 100 mg mL-1 . 2D nuclear magnetic resonance (NMR) analysis and molecular dynamics (MD) are used to study this phenomenon. The addition of 30% dimethyl sulfoxide (DMSO) to the α-tocopherol/CTX solution improves its working viscosity and enhances CTX permeation through human skin in vitro (over 5 µg cm-2 within 24 h), while no detectable drug permeates when CTX is dissolved in α-tocopherol alone. In a transepidermal water loss assay, the barrier impairment induced by CTX in 30% DMSO in α-tocopherol, but not in pure DMSO, is reversible 8 h after the formulation removal from the skin surface. Antitumor efficacy of the topical CTX formulation is evaluated in nude mice bearing A431 human squamous carcinoma skin cancer xenografts. With topical application of concentrated CTX solutions (75 mg mL-1 ), tumor growth is significantly suppressed compared to lower concentration groups (0, 25, or 50 mg mL-1 CTX). Taken together, these findings show that topical delivery of CTX using a DMSO and α-tocopherol solvent warrants further study as a treatment for skin malignancies.

Enzymatic polymerization of enantiomeric L-3,4-dihydroxyphenylalanine into films with enhanced rigidity and stability.

L-3,4-dihydroxyphenylalanine is an important molecule in the adhesion of mussels, and as an oxidative precursor of natural melanin, it plays an important role in living system. Here, we investigate the effect of the molecular chirality of 3,4-dihydroxyphenylalanine on the properties of the self-assembled films by tyrosinase-induced oxidative polymerization. The kinetics and morphology of pure enantiomers are completely altered upon their co-assembly, allowing the fabrication of layer-to-layer stacked nanostructures and films with improved structural and thermal stability. The different molecular arrangements and self-assembly mechanisms of the L+D-racemic mixtures, whose oxidation products have increased binding energy, resulting in stronger intermolecular forces, which significantly increases the elastic modulus. This study provides a simple pathway for the fabrication of biomimetic polymeric materials with enhanced physicochemical properties by controlling the chirality of monomers.

Self-Assembly of Peptide-Lipid Nanoparticles for the Efficient Delivery of Nucleic Acids.

A transfection formulation is successfully developed to deliver nucleic acids by adding an auxiliary lipid (DOTAP) to the peptide, and the transfection efficiency of pDNA reaches 72.6%, which is close to Lipofectamine 2000. In addition, the designed KHL peptide-DOTAP complex exhibits good biocompatibility by cytotoxicity and hemolysis analysis. The mRNA delivery experiment indicates that the complex had a 9- or 10-fold increase compared with KHL or DOTAP alone. Intracellular localization shows that KHL/DOTAP can achieve good endolysosomal escape. Our design provides a new platform for improving the transfection efficiency of peptide vectors.

Peptidyl Virus-Like Nanovesicles as Reconfigurable "Trojan Horse" for Targeted siRNA Delivery and Synergistic Inhibition of Cancer Cells.

The self-assembly of peptidyl virus-like nanovesicles (pVLNs) composed of highly ordered peptide bilayer membranes that encapsulate the small interfering RNA (siRNA) is reported. The targeting and enzyme-responsive sequences on the bilayer's surface allow the pVLNs to enter cancer cells with high efficiency and control the release of genetic drugs in response to the subcellular environment. By transforming its structure in response to the highly expressed enzyme matrix metalloproteinase 7 (MMP-7) in cancer cells, it helps the siRNA escape from the lysosomes, resulting in a final silencing efficiency of 92%. Moreover, the pVLNs can serve as reconfigurable "Trojan horse" by transforming into membranes triggered by the MMP-7 and disrupting the cytoplasmic structure, thereby achieving synergistic anticancer effects and 96% cancer cell mortality with little damage to normal cells. The pVLNs benefit from their biocompatibility, targeting, and enzyme responsiveness, making them a promising platform for gene therapy and anticancer therapy.

Coordination-Induced Self-Assembly of a Dipeptide into Multifunctional Chiral Nanostructures.

Short peptides could be used as chiral motifs to self-assemble into various artificial nanostructures with supramolecular or nanoscale chirality, but their applications still need to be expanded. Here, under the mediation of metal ions, the ferrocene-diphenylalanine (Fc-LFLF) peptide can self-assemble into various chiral nanostructures, including right-handed helical microflowers mediated by Cu2+, left-handed nanofibers mediated by Ag+, and right-handed nanofibers mediated by Zn2+ and Cd2+. Meanwhile, the gold nanoparticles could be mineralized and deposited on Cu2+/Fc-LFLF microflowers to form AuNPs@Cu2+/Fc-LFLF, which showed significantly improved catalytic activity. The Ag+ could be further mineralized on the peptide nanofibers to form AgNPs@Fc-LFLF, showing an excellent antibacterial effect. Overall, this study provides new insights into the chiral self-assembly of short peptides and demonstrates that the chiral peptide-metal assemblies may have broad prospects in the fields of biocatalysis and antimicrobials.

Bioinspired porphyrin-peptide supramolecular assemblies and their applications.

Inspired by the hierarchical chiral assembly of porphyrin-proteins in photosynthetic systems, the hierarchical self-assembly of porphyrin-amino acids/peptides provides a novel strategy for constructing functional materials. How to artificially simulate the assembly of porphyrins, proteins, and other cofactors in the photosynthesis system to obtain persistent strong light capture, charge separation and catalytic reactions has become an important concern in the construction of biomimetic photosynthesis systems. This paper summarizes the different assembly strategies adopted in recent years, the effects of driving forces on self-assembly, and the application of porphyrin-peptides in catalysis and biomedicine, and briefly discusses the challenges and prospects for future research.

Pickering Emulsions Stabilized by Lignin/Chitosan Nanoparticles for Biphasic Enzyme Catalysis.

In this study, we construct a green and high-performance platform using Pickering emulsions for biphasic catalysis. The oil-in-water Pickering emulsions stabilized by the lignin/chitosan nanoparticles (Lig/Chi NPs) have great stability and alkali resistance, showing pH-responsive reversible emulsification and demulsification which can be recycled at least three times. The Pickering emulsion also has fluorescence and wide availability to different oil-to-water volume ratios, types of oil, storage times, temperatures, and ion concentrations. When this system is applied to the lipase-catalyzed reaction for the hydrolysis of p-nitrophenol palmitate, it will provide stable and large oil-water reaction interface areas, and the negatively charged lipase will enrich at the emulsion interface by electrostatic adsorption of the positively charged Lig/Chi NPs to achieve immobilization (lipase-Lig/Chi NPs). The reaction conversion rate can reach nearly 100% in 30 min, which is nearly three times higher than that of the conventional two-phase system. Moreover, the lipases in Pickering emulsion stabilized by Lig/Chi NPs exhibit great recyclability because of the protection of Lig/Chi NPs.