LOCK-AND-KEY INTERACTIONS BETWEEN CHIRAL NANOPARTICLES AND PROTEINS

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

Ultrasmall particles with nanoscale dimensions, often referred to as nanoparticles, are potent new agents for treatment of cancers, preservation of vaccines and inhibition of harmful otherwise untreatable bacterial infections. The geometric shape of the nanoparticles plays a significant role in their medical efficacy but understanding how to make particles with complex shapes, which serve the patients well, is also critical. This project will extend the concept of lock-and-key interactions between biomolecules to the interactions between nanoparticles and proteins. Essential for this study is the common geometric property of nanoparticles and proteins known as chirality. This property defines whether the geometrical objects of complex shapes can fit each other. The importance of chirality for geometrical matches between complex shapes can be exemplified by the helices wrapping around each other, which is foundational for biomolecules. This project will establish a general methodology to design nanoparticles with complex shapes based on mathematical measures of chirality and machine learning. The overarching goal of this project is to provide medical researchers with ready-to-use algorithms predicting the shape of nanoparticles forming lock-and-key complexes with proteins and chemical methods for their synthesis. Considering the universal importance of the lock-and-key interactions in biology, the toolbox based on chirality will be adapted and universally applicable for biotechnology, biocatalysis, and bioremediation. The educational mission of the project will include training a broad range of young scientists from high school students to postdoctoral researchers in the applications of nanoparticles for medical needs. This will increase the competitiveness of the United States in the development of innovative medical technologies. The principal investigator will also mentor young colleagues from groups traditionally under-represented in STEM fields within the Detroit area, communicating the importance of chirality in biology and nanotechnology. The University of Michigan team will develop a set of unifying descriptors for nanoparticles and proteins using highly biocompatible nanoparticles from graphene, amorphous carbon, and cerium oxide. Project goals are to establish comprehensive machine learning models for the prediction of nanoparticle-protein complexes; evaluate molecular and nanoscale chirality as a significant geometric parameter for the formation of nanoparticle-protein complexes; and develop methodologies for designing viable nanoparticle candidates for biological and biomedical applications. Diverse types of nanoparticles will be used to introduce chirality at molecular, nanoscale, and sub-nanoscale levels, which will be quantified using the newly developed approach of multiscale chirality vectors. The chirality vectors will serve as a general engineering principle for designing nanoparticles with complex shapes depending on the synthetic approach. The machine learning algorithms and state-of-the-art neural networks will be evaluated for the predictive synthesis of chiral nanoparticles starting from the twisted graphene nanoplatelets. The generality of the design methodology will be evaluated for amorphous carbon and cerium oxide nanoparticles. The predictive power of chiral measures will be demonstrated for lock-and-key complexes between nanoparticles and amyloid proteins of antibiotic-resistant bacteria. The practical significance of this project will be evaluated by the efficacy of inhibition of bacterial infections utilizing amyloid fibrils as nanoscale armor for their biofilms. The broader impact of the project will include a strong outreach program, supported by the extensive history of the PI in collaborating with young scientists from all backgrounds. Specifically, the PI will incorporate African American students from underprivileged backgrounds from the Detroit area in this project. Outreach activities will be focused on promoting teaching and training of high school students as well as on mentoring young colleagues from universities with limited research capabilities in the Detroit area. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.