20 Search Results

Supramolecular hydrogels that mimic the extracellular matrix (ECM) represent promising materials for tissue engineering and drug delivery. However, conventional hydrogels formed via the self-assembly of natural or synthetic building blocks often face a trade-off between biological functionality and biochemical stability, limiting their utility in long-term or protease-rich environments. Peptoids, a class of peptide-inspired, sequence-defined polymers, offer a compelling alternative due to their exceptional proteolytic resistance and bioactivity. Despite this potential, the development of supramolecular peptoid hydrogels has been hindered by the absence of backbone hydrogen bond donors, which limits long-range ordering necessary for efficient hydrogel formation. This work describes amore » short peptoid functionalized at the N-terminus with an octyl chain that readily self-assembles into hydrogels. Hydrophobic interactions among pendant octyl groups promote directional peptoid packing into highly ordered nanosheets, which interconnect to form a porous hydrogel network. These hydrogels exhibit tunable viscoelasticity, shear-thinning, and self-healing properties, enabling their use as inks for extrusion-based 3D printing. They support NIH-3T3 fibroblast adhesion, spreading, and proliferation, maintaining greater than 95% cell viability over 4 days. Moreover, the hydrogels retain their macroscopic integrity under protease-rich conditions, enabling sustained cargo release and uniform cellular uptake. Together, this study demonstrates a class of supramolecular peptoid hydrogelators that integrate biocompatibility, 3D printability, and proteolytic stability, providing a versatile platform for ECMmimetic scaffolds in regenerative medicine and long-term therapeutic delivery.« less

As peptoids (N-substituted glycines) continue to gain popularity as a class of biomimetic polymers, the importance and demand for accurate force fields in molecular simulations also grow. Building on the vacuum-optimized Systematic and Extensible Force Field for Peptoids (STEPs) force field, here we present STEPs-SOL, a novel peptoid force field parametrization that effectively incorporates solvent effects to enhance the accuracy of peptoid simulations. The development of STEPs-SOL is based on the need for precise electrostatic modeling achieved through solvent-specific partial charge optimization. Here, our systematic approach significantly improves agreement with experimental measurements, reducing the mean absolute error in cis/trans ratiomore » predictions (ΔG_c/t) by an average of 38% across multiple peptoid residues and solvent environments. This improved parametrization addresses computational challenges associated with nonbonded energies while maintaining a workflow that relies on high-level quantum mechanical data rather than depending solely on limited experimental equilibrium properties. By evaluating the effects of conformational bias in restrained electrostatic potential (RESP) charge generation and examining their impact on peptoid conformations in various solvents, we enhance our understanding of peptoid structural dynamics while providing a more accurate modeling framework.« less

Combining the advantages of structural programmability in sequence-defined biomimetic molecules and the controllable packing geometry in nanoparticle superlattices, we demonstrate a self-assembled organic–inorganic superlattice whose structure can be altered with the slightest change in the sequence of the organic counterpart. Here, oleate-coated CdS quantum dots (QDs) form a square-packed superlattice with a 1:1 molar equivalence of a diblock amphiphilic peptoid (Nbrpe6Dig) in chloroform. In contrast, no apparent structure is observed in the organic solvent alone. Based on theoretical evidence, we show that the assembly is a binary superlattice where both the CdS QDs and the peptoids serve as building blocksmore » and further predict a correlation between the superlattice structure and the peptoid sequence. The computationally guided prediction is validated by experiments where superlattice transformation is observed with modified peptoids. Furthermore, the mechanism identified in our work inspires new ways to control and tune organic–inorganic hybrid nanomaterial self-assembly.« less

The extensive deposits of calcium carbonate (CaCO₃) generated by marine organisms constitute the largest and oldest carbon dioxide (CO₂) reservoir. These organisms utilize macromolecules like peptides and proteins to facilitate the nucleation and growth of carbonate minerals, serving as an effective method for CO₂ sequestration. However, the precise mechanisms behind this process remain elusive. In this study, we report the use of sequence-defined peptoids, a class of peptidomimetics, to achieve the accelerated calcite step growth kinetics with the molecular level mechanistic understanding. By designing peptoids with hydrophilic and hydrophobic blocks, we systematically investigated the acceleration in step growth rate ofmore » calcite crystals using in situ atomic force microscopy (AFM), varying peptoid sequences and concentrations, CaCO₃ supersaturations, and the ratio of Ca²⁺/ HCO₃-. Mechanistic studies using NMR, three-dimensional fast force mapping (3D FFM), and isothermal titration calorimetry (ITC) were conducted to reveal the interactions of peptoids with Ca²⁺ and HCO₃- ions in solution, as well as the effect of peptoids on solvation and energetics of calcite crystal surface. Our results indicate the multiple roles of peptoid in facilitating HCO₃- deprotonation, Ca²⁺ desolvation, and the disruption of interfacial hydration layers of the calcite surface, which collectively contribute to a peptoid-induced acceleration of calcite growth. These findings provide guidelines for future design of sequence-specific biomimetic polymers as crystallization promoters, offering potential applications in environmental remediation (such as CO₂ sequestration), biomedical engineering, and energy storage where fast crystallization is preferred.« less

Cryogenic transmission electron microscopy (cryo–TEM) combined with single particle analysis (SPA) is an emerging imaging approach for soft materials. However, the accuracy of SPA–reconstructed nanostructures, particularly those formed by synthetic polymers, remains uncertain due to potential packing heterogeneity of the nanostructures. In this study, the combination of molecular dynamics (MD) simulations and image simulations is utilized to validate the accuracy of cryo–TEM 3D reconstructions of self–assembled polypeptoid fibril nanostructures. Using CryoSPARC software, image simulations, 2D classifications, ab initio reconstructions, and homogenous refinements are performed. By comparing the results with atomic models, the recovery of molecular details is assessed, heterogeneous structuresmore » are identified, and the influence of extraction location on the reconstructions is evaluated. In conclusion, these findings confirm the fidelity of single particle analysis in accurately resolving complex structural characteristics and heterogeneous structures, exhibiting its potential as a valuable tool for detailed structural analysis of synthetic polymers and soft materials.« less

Bacterial infections have been a serious threat to mankind throughout history. Natural antimicrobial peptides (AMPs) and their membrane-disruption mechanism have generated an immense interest in the design and development of synthetic mimetics that could overcome the intrinsic drawbacks of AMPs, such as their susceptibility to proteolytic degradation. Herein, by exploiting the self-assembly and pore-forming capabilities of sequence-defined peptoids, we discovered a new family of low molecular weight peptoid antibiotics that exhibit excellent broad-spectrum activity and high selectivity toward a panel of clinically significant Gram-positive and Gram-negative bacterial strains, including vancomycin-resistant E. faecalis (VREF), methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermidismore » (MRSE), E. coli, P. aeruginosa, and K. pneumoniae. Tuning peptoid sidechain chemistry and structure enabled us to tune the efficacy of antimicrobial activity. Mechanistic studies using Transmission Electron Microscopy (TEM), bacterial membrane depolarization and lysis, and time-kill kinetics assays along with molecular dynamics simulations reveal that these peptoids kill both Gram-positive and Gram-negative bacteria through a membrane-disruption mechanism. In conclusion, these robust and biocompatible peptoid-based antibiotics can provide a valuable tool for combating the emerging drug resistance.« less

Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clusteringmore » a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs.« less

Mineral-polymer composites found in nature exhibit exceptional structural properties essential to their function, and transferring these attributes to the synthetic design of functional materials holds promise across various sectors. Biomimetic fabrication of nanocomposites introduces new pathways for advanced material design and explores biomineralization strategies. This study presents a novel approach for producing single platelet nanocomposites composed of CaCO₃ and biomimetic peptoid (N-substituted glycines) polymers, akin to the bricks found in the brick-and-mortar structure of nacre, the inner layer of certain mollusc shells. The significant aspect of the proposed strategy is the use of organic peptoid nanosheets as the scaffolds formore » brick formation, along with their controlled mineralization in solution. Here, we employ the B28 peptoid nanosheet as a scaffold, which readily forms free-floating zwitterionic bilayers in aqueous solution. The peptoid nanosheets were mineralized under consistent initial conditions (σ_calcite = 1.2, pH 9.00), with variations in mixing conditions and supersaturation profiles over time aimed at controlling the final product. Nanosheets were mineralized in both feedback control experiments, where supersaturation was continuously replenished by titrant addition and in batch experiments without a feedback loop. Complete coverage of the nanosheet surface by amorphous calcium carbonate was achieved under specific conditions with feedback control mineralization, whereas vaterite was the primary CaCO₃ phase observed after batch experiments. Thermodynamic calculations suggest that time-dependent supersaturation profiles as well as the spatial distribution of supersaturation are effective controls for tuning the mineralization extent and product. We anticipate that the control strategies outlined in this work can serve as a foundation for the advanced and scalable fabrication of nanocomposites as building blocks for nacre-mimetic and functional materials.« less

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirusmore » strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.« less