Design of Robust and Responsive Protein-Polymer Bioconjugates guided by Magnetic Resonance
Abstract
Protein based materials have numerous defense relevant applications including as potent biosensors capable of alerting the soldier of environmental threats or report.ing on the physical cond.ition of the solider, as catalysts for the synthesis of complex molecules, and in remediation of toxins that can be a threat to the soldier. Despite the excellent potential of proteins in these applications, the limited stability and performance under challenging condit.ions severely limits the use of proteins under harsh conditions such as extremes of pH, temperature or environments rich in organic compounds. To overcome limitations in protein performance under challenging conditions, attachment of synthetic molecules, such as synthetic polymers, to create a protein polymer bioconjugate, can enhance the performance of a protein under extreme conditions. Synthetic macromolecules offer boundless flexibility to augment performance, giving flexibility over shape, structure, functionality and size of the molecule. Despite the excellent potential of polymer bioconjugates to stabilize proteins under harsh conditions, there are no general blueprints or scientific principles to guide the rational design of the synthetic molecule to enhance the performance of the biological macromolecule. The lack of blueprints for designing synthetic molecules for enhanced bioconjugates stems from a lack of understanding of how the synthetic part of the biohybrid interacts with the biological component. This leads to the core research question in this proposal: How can polymers be rationally chosen to modulate and enhance the act.ivity and stability of a protein-polymer bioconjugate, especially under harsh conditions? This project will utilize a recently developed method, based on magnetic resonance, to evaluate the relative conformations and interactions of the synthetic and biological components of protein-polymer bioconjugates. This magnetic resonance method, called paramagnetic relaxation enhancement nuclear magnetic spectroscopy (PRE NMR), gives with atomic precision the relative distance of a labeled polymer to each amino acid in the protein. This effort will utilize the PRE NMR method across a library of bioconjugates with each member of the library being composed of distinct and well defined polymer structures and functionalities coupled to one of an array of proteins, generating data that can be used to design new bioconjugates. This project is d.ivided into 3 thrusts: I. Evaluate how polymer structure and functionality impacts its ability to interact with protein surfaces across a library of proteins. 2. Correlate bioconjugate activity and stability with proximities between the protein and the polymer across polymer structure and functionality. 3. Drive and measure stimulus-induced polymer regulation of bioconjugate activity and stability. The PRE NMR method is broadly applicable to a diverse range of proteins, making the technique as well as the insights derived from this fundamental study broadly applicable to the rational design of responsive and precision made bioconjugates with applications in both fundamental science as well as complex applications that have not yet being realized due to the fragility of proteins.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 08, 2023
- Source ID
- W911NF2310114
Entities
People
- Dominik Konkolewicz
Organizations
- Army Contracting Command
- Miami University
- United States Army