Objectives and workplan
Chiral-Pro
Project
The CHIRAL-PRO project, titled “Handshake Complexes between Chiral Nanoparticles and Proteins”, aims to develop a systematic methodology for engineering chiral nanoparticles (NPs) with exceptional optical activity, enabling precise enantioselective interactions with biological structures such as proteins and amyloid fibrils. By uncovering the role of chirality in molecular recognition, the project will facilitate the programmed assembly of optically active nanofibres and explore applications in biosensing and metamaterials. This research seeks to deepen our understanding of chiral nanostructures and provide a versatile toolkit for designing them with targeted properties.
The project has received a prestigious ERC Synergy Grant with a total funding of 9.27 million euros. The ERC Synergy Grants, part of the EU’s Horizon Europe research and innovation program, foster the collaboration between outstanding researchers from different disciplines and countries, enabling them to combine their expertise, knowledge and resources through high-risk research projects to push the boundaries of scientific discovery.
Chirality, the property of lacking mirror symmetry, is a feature of both biological and synthetic materials. While advancements in chiral inorganic nanoparticles have demonstrated their potential across various fields, their tailored design for biological interactions remains a challenge. The field of chirality has seen a strong rejuvenation due to the observation of nanoscale chirality in plasmonic nanoparticles. Much research in this field has been related to chiral nanostructures formed by the directed self-assembly of gold nanorods on various chiral templates. More recent work has demonstrated the possibility of employing the well-known seeded-growth strategy to endow colloidal nanoparticles with chiral features in the presence of molecular chiral inducers. These concepts open up a wide range of possibilities, by playing around with the variety of potential chiral inducers and co-surfactants, seed morphologies and metal compositions.
By developing nanoparticles with tailored optical properties, the project aims to achieve precise enantioselective interactions with biological molecules. The final goal will be to use IA tools to predict the optimal morphology of chiral nanoparticles for selective and strong binding with proteins and protein assemblies. This could lead to significant advancements in the detection of diseases exemplified by colon cancer and Alzheimer’s disease.
In addition to groundbreaking advancements in fundamental research, the high gain of this work can be found in the generation of a toolbox enabling the scientific community to shift from guessing to precise design of chiral nanostructures with predefined properties. The outcome of the project will boost success in the future implementation of applications for chiral NPs, as will be shown in the selected case studies conducted throughout the project.
CHIRAL-PRO is expected to greatly accelerate the development of NPs with handshake match of chiral features to those on proteins for amyloid detection, amyloid fibrillation inhibitors, metamaterials, contrast agents, nanoscale adjuvants, enzyme mimics and antimicrobial agents.
Objectives
To reach the final objective of developing a methodology to create predefined, (multi-)chiral gold NPs with enhanced optical activity for applications in the fields of metamaterials and disease detection, the following intermediate objectives have been defined:
To achieve
To achieve a fundamental understanding of chiral growth mechanisms based on innovative (combinations of) chiral inducers, supported by electron tomography, in situ TEM characterization, and machine-learning (ML) predictions, leading to controlled, flexible and reproducible synthesis of NPs with multiscale chirality.
To understand
To understand which morphological features of chiral Au NPs contribute to their chiroptical activity, and how the single particle chiroptical activity of many particles in an inevitably polydisperse sample translates into the ensemble level chiroptical activity.
To enable
To enable high-throughput, 3D TEM characterization of the structure of chiral NPs, down to the atomic level and at least 1000 times faster than state-of-the-art electron tomography, without compromising image resolution.
To develop
To develop unified structural and chirality descriptors applicable to NPs, proteins, and fibrils. These descriptors will be calculated from TEM data, PDB files and spectroscopy data, and used as input for ML algorithms, to predict the formation of NP complexes with proteins and fibrils.
Besides these objectives, the project will perform a proof-of-concept application to the following case studies:
Case study 1
Fast detection of amyloids in complex biological environments: Rapid spectroscopic (circular dichroism and Raman optical activity) detection of disease-related protein assemblies like bacterial amyloids, suitable for accurate diagnosis of disease stage in biofluids and biofilms.
Case study 2
Self-assembly of helical metamaterials: NP-protein complexes and fibrillary assemblies with giant optical activity arising from chirality at multiple scales, various degrees of twisting and metamaterial-like properties.
Workplan
The project research plan is built upon the integration of the following work packages (WP), addressing both the fundamental and practical objectives defined above:
- Understand and control chiral NPs growth mechanisms.
- Establish the structure-property connections for chiral NPs, leading to high chiroptical activity.
- Develop novel high-throughput 3D TEM characterization techniques.
- Train ML predictions models of the NP morphological features that interact with specific protein or fibers.
- Demonstrate protein-directed binding of chiral NPs into chiral nanofibers.