The design of novel cancer drug nanocarriers is critical in the framework of cancer therapeutics. Nanomaterials are gaining increased interest as cancer drug delivery systems. Self-assembling peptides constitute an emerging novel class of highly attractive nanomaterials with highly promising applications in drug delivery, as they can be used to facilitate drug release and/or stability while reducing side effects. Here, we provide a perspective on peptide self-assembled nanocarriers for cancer drug delivery and highlight the aspects of metal coordination, structure stabilization, and cyclization, as well as minimalism. We review particular challenges in nanomedicine design criteria and, finally, provide future perspectives on addressing a portion of the challenges via self-assembling peptide systems. We consider that the intrinsic advantages of such systems, along with the increasing progress in computational and experimental approaches for their study and design, could possibly lead to novel classes of single or multicomponent systems incorporating such materials for cancer drug delivery.

Peptide self-assembly has attracted extensive interest in the field of eco-friendly optoelectronics and bioimaging due to its inherent biocompatibility, intrinsic fluorescence, and flexible modulation. However, the practical application of such materials was hindered by the relatively low quantum yield of such assemblies. Here, inspired by the molecular structure of BFPms1, we explored the "self-assembly locking strategy" to design and manipulate the assembly of metal-stabilized cyclic(L-histidine-D-histidine) into peptide material with the high fluorescence efficiency. We used this bioorganic material as an emissive layer in photo- and electro-luminescent prototypes, demonstrating the feasibility of utilizing self-assembling peptides to fabricate a bio-integrated microchip that incorporates eco-friendly and tailored optoelectronic properties. We further employed a “self-encapsulation” strategy for constructing an advanced nanocarrier with integrated in situ monitoring. The strategy of the supramolecular capture of functional components exemplifies the use of bioinspired organic chemistry to provide frontiers of smart materials, potentially allowing a better interface between sustainable optoelectronics and biomedical applications.

We describe the development and testing of ab initio derived, AMBER ff03 compatible charge parameters for a large library of 147 noncanonical amino acids including β- and N-methylated amino acids for use in applications such as protein structure prediction and de novo protein design. The charge parameter derivation was performed using the RESP fitting approach. Studies were performed assessing the suitability of the derived charge parameters in discriminating the activity/inactivity between 63 analogs of the complement inhibitor Compstatin on the basis of previously published experimental IC₅₀ data and a screening procedure involving short simulations and binding free energy calculations. We found that both the approximate binding affinity (K*) and the binding free energy calculated through MM-GBSA are capable of discriminating between active and inactive Compstatin analogs, with MM-GBSA performing significantly better. Key interactions between the most potent Compstatin analog that contains a noncanonical amino acid are presented and compared to the most potent analog containing only natural amino acids and native Compstatin. We make the derived parameters and an associated web interface that is capable of performing modifications on proteins using Forcefield_NCAA and outputting AMBER-ready topology and parameter files freely available for academic use at http://selene.princeton.edu/FFNCAA. The forcefield allows one to incorporate these customized amino acids into design applications with control over size, van der Waals, and electrostatic interactions.

The aggregation of amyloid-β (Aβ) peptides into senile plaques is a hallmark of Alzheimer’s disease (AD) and is hypothesized to be the primary cause of AD related neurodegeneration. Previous studies have shown the ability of curcumin to both inhibit the aggregation of Aβ peptides into oligomers or fibrils and reduce amyloids in vivo. Despite the promise of curcumin and its derivatives to serve as diagnostic, preventative, and potentially therapeutic AD molecules, the mechanism by which curcumin and its derivatives bind to and inhibit Aβ fibrils’ formation remains elusive. Here, we investigated curcumin and a set of curcumin derivatives in complex with a hexamer peptide model of the Aβ_1–42 fibril using nearly exhaustive docking, followed by multi-ns molecular dynamics simulations, to provide atomistic-detail insights into the molecules’ binding and inhibitory properties. In the vast majority of the simulations, curcumin and its derivatives remain firmly bound in complex with the fibril through primarily three different principle binding modes, in which the molecules interact with residue domain ₁₇LVFFA₂₁, in line with previous experiments. In a small subset of these simulations, the molecules partly dissociate the outermost peptide of the Aβ_1–42 fibril by disrupting β-sheets within the residue domain ₁₂VHHQKLVFF₂₀. A comparison between binding modes leading or not leading to partial dissociation of the outermost peptide suggests that the latter is attributed to a few subtle key structural and energetic interaction-based differences. Interestingly, partial dissociation appears to be either an outcome of high affinity interactions or a cause leading to high affinity interactions between the molecules and the fibril, which could partly serve as a compensation for the energy loss in the fibril due to partial dissociation. In conjunction with this, we suggest a potential inhibition mechanism of Αβ_1–42 aggregation by the molecules, where the partially dissociated ₁₆KLVFF₂₀ domain of the outermost peptide could either remain unstructured or wrap around to form intramolecular interactions with the same peptide’s ₂₉GAIIG₃₃ domain, while the molecules could additionally act as a patch against the external edge of the second outermost peptide’s ₁₆KLVFF₂₀ domain. Thereby, individually or concurrently, these could prohibit fibril elongation.