Leveraging Peptide Sequence Modification to Promote Assembly of Chiral Helical Gold Nanoparticle Superstructures.

Peptide conjugate molecules comprising a gold-binding peptide (e.g., AYSSGAPPMPPF) attached to an aliphatic tail have proven to be powerful agents for directing the synthesis and assembly of gold nanoparticle superstructures, in particular chiral helices having interesting plasmonic chiroptical properties. The composition and structure of these molecular agents can be tailored to carefully tune the structure and properties of gold nanoparticle single and double helices. To date, modifications to the ß-sheet region (AYSSGA) of the peptide sequence have not been exploited to control the metrics and assembly of such superstructures. We report here that systematic peptide sequence variation in a series of gold-binding peptide conjugate molecules can be leveraged not only to affect the assembly of peptide conjugates but also to control the synthesis, assembly, and optical properties of gold nanoparticle superstructures. Depending upon the hydrophobicity of a single-amino acid variant, the conjugates yield either dispersed gold nanoparticles or helical superstructures. These results provide evidence that subtle changes to peptide sequence, via single-amino acid variation in the ß-sheet region, can be leveraged to program structural control in chiral gold nanoparticle superstructures.

Tuning the Structure and Chiroptical Properties of Gold Nanoparticle Single Helices via Peptide Sequence Variation.

Just as peptide function is determined by the position, sequence, and overall arrangement of constituent amino acids, the optical properties of nanoparticle (NP) assemblies are influenced by the size, dimensions, and arrangement of constituent NPs. In this work, we demonstrate that peptide sequence can be programmed to direct the structure and chiroptical activity of chiral helical gold NP (AuNP)superstructures, a growing class of chiral nanomaterials with potential in sensing, detection, and optics-based applications. Gold-binding peptide conjugate families, C18-(PEPAuM,x)2 and C18-(PEPAuM-ox,x)2, that differ in the position (x = 7, 9, and 11) of methionine (M)/methionine sulfoxide (M-ox) within the peptide sequences (PEPAu = AYSSGAPPMPPF/PEPAuM-ox = AYSSGAPPMoxPPF) are employed to control the aspect ratio and size of AuNPs within helical NP assemblies. Computational modeling reveals that the amino acid variations have a profound effect on peptide-AuNP interactions that ultimately lead to control over NP size. C18-(PEPAuM,x)2 (x = 7, 9, and 11) yield irregular double-helical superstructures comprising spherical AuNPs, while C18-(PEPAuM-ox,x)2 (x = 9, 11) yield single-helical assemblies comprising oblong or rod-shaped AuNPs. Further, component AuNPs are larger when M/M-ox is placed at x = 11, while smaller component AuNPs are observed when M/M-ox is placed at x = 7. Changes in nanoscale structures manifest themselves in observable differences in chiroptical signal intensity. Ultimately, we achieve dramatic variance in the structure and properties of chiral AuNP superstructures via simple molecular-level tuning of peptide primary sequence.

Systematic Adjustment of Pitch and Particle Dimensions within a Family of Chiral Plasmonic Gold Nanoparticle Single Helices.

Systematically controlling the assembly architecture within a class of chiral nanoparticle superstructures is important for fine-tuning their chiroptical properties. Here, we report a family of chiral gold nanoparticle single helices, varying in helical pitch and nanoparticle dimensions, that is assembled using a series of peptide conjugate molecules Cx-(PEPAuM-ox)2 (PEPAuM-ox = AYSSGAPPMoxPPF; x = 16-22). We demonstrate that the aliphatic tail length (i) can be used as a handle to systematically tune the helical pitch from 80 to 130 nm; and (ii) influences the size, shape, and aspect ratio of the component nanoparticles. Certain members of this family of materials exhibit intense plasmonic chiroptical activity. These studies highlight the multiple levels of structural control that can be achieved within a class of chiral nanoparticle superstructures via careful design and selection of peptide conjugate precursor.

Reconstructing the Surface of Gold Nanoclusters by Cadmium Doping.

Atomically precise metal nanoclusters with tailored surface structures are important for both fundamental studies and practical applications. The development of new methods for tailoring the surface structure in a controllable manner has long been sought. In this work, we report surface reconstruction induced by cadmium doping into the [Au23(SR)16]- (R = cyclohexyl) nanocluster, in which two neighboring surface Au atomic sites "coalesce" into one Cd atomic site and, accordingly, a new bimetal nanocluster, [Au19Cd2(SR)16]-, is produced. Interestingly, a Cd(S-Au-S)3 "paw-like" surface motif is observed for the first time in nanocluster structures. In such a motif, the Cd atom acts as a junction which connects three monomeric -S-Au-S- motifs. Density functional theory calculations are performed to understand the two unique Cd locations. Furthermore, we demonstrate different doping modes when the [Au23(SR)16]- nanocluster is doped with different metals (Cu, Ag), including (i) simple substitution and (ii) total structure transformation, as opposed to surface reconstruction for Cd doping. This work greatly expands doping chemistry for tailoring the structures of nanoclusters and is expected to open new avenues for designing nanoclusters with novel surface structures using different dopants.

Peptide-Directed Assembly of Single-Helical Gold Nanoparticle Superstructures Exhibiting Intense Chiroptical Activity.

Chiral nanoparticle assemblies are an interesting class of materials whose chiroptical properties make them attractive for a variety of applications. Here, C18-(PEPAuM-ox)2 (PEPAuM-ox = AYSSGAPPMoxPPF) is shown to direct the assembly of single-helical gold nanoparticle superstructures that exhibit exceptionally strong chiroptical activity at the plasmon frequency with absolute g-factor values up to 0.04. Transmission electron microscopy (TEM) and cryogenic electron tomography (cryo-ET) results indicate that the single helices have a periodic pitch of approximately 100 nm and consist of oblong gold nanoparticles. The morphology and assembled structure of C18-(PEPAuM-ox)2 are studied using TEM, atomic force microscopy (AFM), Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD) spectroscopy, X-ray diffraction (XRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. TEM and AFM reveal that C18-(PEPAuM-ox)2 assembles into linear amyloid-like 1D helical ribbons having structural parameters that correlate to those of the single-helical gold nanoparticle superstructures. FTIR, CD, XRD, and ssNMR indicate the presence of cross-ß and polyproline II secondary structures. A molecular assembly model is presented that takes into account all experimental observations and that supports the single-helical nanoparticle assembly architecture. This model provides the basis for the design of future nanoparticle assemblies having programmable structures and properties.

Thrombospondin-1 proteomimetic polymers exhibit anti-angiogenic activity in a neovascular age-related macular degeneration mouse model.

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the developed world. Current therapy includes monthly intraocular injections of anti-VEGF antibodies, which are ineffective in up to one third of patients. Thrombospondin-1 (TSP1) inhibits angiogenesis via CD36 binding, and its down-regulated expression is negatively associated with the onset of nAMD. Here, we describe TSP1 mimetic protein-like polymers (TSP1 PLPs). TSP1 PLPs bind CD36 with high affinity, resist degradation, show prolonged intraocular half-lives (13.1 hours), have no toxicity at relevant concentrations in vivo (40 µM), and are more efficacious in ex vivo choroidal sprouting assays compared to the peptide sequence and Eylea (aflibercept), the current standard of care anti-VEGF treatment. Furthermore, PLPs exhibit superior in vivo efficacy in a mouse model for nAMD compared to control PLPs consisting of scrambled peptide sequences, using fluorescein angiography and immunofluorescence. Since TSP-1 inhibits angiogenesis by VEGF-dependent and independent mechanisms, TSP1 PLPs are a potential therapeutic for patients with anti-VEGF treatment-resistant nAMD.

Construction of Chiral, Helical Nanoparticle Superstructures: Progress and Prospects.

Chiral nanoparticle (NP) superstructures, in which discrete NPs are assembled into chiral architectures, represent an exciting and growing class of nanomaterials. Their enantiospecific properties make them promising candidates for a variety of potential applications. Helical NP superstructures are a rapidly expanding subclass of chiral nanomaterials in which NPs are arranged in three dimensions about a screw axis. Their intrinsic asymmetry gives rise to a variety of interesting properties, including plasmonic chiroptical activity in the visible spectrum, and they hold immense promise as chiroptical sensors and as components of optical metamaterials. Herein, a concise history of the foundational conceptual advances that helped define the field of chiral nanomaterials is provided, and some of the major achievements in the development of helical nanomaterials are highlighted. Next, the key methodologies employed to construct these materials are discussed, and specific merits that are offered by each assembly methodology are identified, as well as their potential disadvantages. Finally, some specific examples of the emerging applications of these materials are discussed and some areas of future development and research focus are proposed.

Triblock peptide-oligonucleotide chimeras (POCs): programmable biomolecules for the assembly of morphologically tunable and responsive hybrid materials.

Triblock peptide-oligonucleotide chimeras (POCs) consisting of peptides and oligonucleotides interlinked by an organic core are presented and their assembly behaviour is investigated. Several factors influence POC assembly, resulting in the formation of either vesicles or fibres. Design rules are introduced and used to predict and alter POC assembly morphology.