Multi-resolution computational probes of biomolecular structure and function

The National Institute of General Medical Sciences awarded the University of Illinois $2,101,232 on August 10, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop quantitative computational approaches that probe diverse biological processes and relate their outcomes to molecular structure and motion.

The project will develop computational methods ranging from atomistic molecular dynamics to continuum simulations, guided by unmet needs in basic biomedical research. In collaboration with three structural biology laboratories, the recipient will develop computational probes to determine the structure of genomes in self-assembled viruses and their transformation during maturation processes. In collaboration with single-molecule experimentalists, computational probes will be designed to determine the biophysical forces driving genome ejection from viruses and subsequent genome organization in host cells. The project will also leverage advances in structure prediction methods to describe the behavior of genome-scale DNA interacting with protein complexes.

The award is a Project Grant under the assistance type designation. Performance occurs at the University of Illinois, Urbana, Illinois, with an ultimate completion date of July 31, 2030.

Abstract

Knowing exactly how biological processes arises from a collection of small unanimated molecules is one of the grand questions of modern science. This question, however, is not just a mere curiosity, not a trending topic, and not an intellectual everest. Answering this question is necessary to understand disease and improve health. That is, we must know how ailments arise from the behavior of molecules, because the behavior of molecules is what we can affect with our current therapeutics. The overarching goal of this project is to develop quantitative computational approaches that can probe diverse biological processes and relate their outcomes to the structure and motion of the molecules that comprise them. Just as the scales of such processes range from the microscopic motion of atoms to the collective responses of cellular organelles, these computational probes encompass computational methods that range from atomistic molecular dynamics to continuum simulations. Development of such computational probes is guided by unmet needs in several areas of basic biomedical research. While experiment has provided a wealth of information about the structure of viral protein capsids, much less is known about the structure and biophysical properties of their genomes. In collaboration with three leading structural biology labs, this project will develop computational probes to determine the structure of genomes in self-assembled viruses and their transformation during the maturation processes. In collaboration with single molecule experimentalists, computational probes will be developed to determine the biophysical forces driving genomes' ejection from a virus and their subsequent organization in a host cell. Leveraging recent advances in structure prediction methods, computational probes will be designed to describe the behavior of a genome-scale DNA interacting with a constellation of DNA binding proteins and undergoing a replication process. Computational methods will be developed to calibrate and interpret nanoscale probes of biomolecular interactions, such as DNA origami probes of intermolecular forces and nanopore probes of protein-protein and protein-drug interactions. The multi-resolution computational probes developed through this project will be disseminated broadly to the biomedical community as modules of popular software packages, step-by-step tutorials serving as practical guides to typical applications and through hands-on workshop instructions.