Development and Application of Multi-scale Modeling to Biomolecular Association

Protein regulation is vital for maintaining cellular function. Many proteins are regulated by interactions between two proteins, where a small molecule, termed molecular glue, binds at the interface between them. Molecular glues play a crucial role in cellular processes by facilitating these interactions, thereby helping to regulate cellular function more efficiently.

Additionally, in nature, proteins often co-localize or assemble to accelerate biomolecular processes. In this project, the investigator will computationally simulate protein-glue-protein binding and dissociation to understand how a molecular glue mediates complex formation and why co-localizing proteins can facilitate their functions. Through iterations of experiments with collaborators and computation, the research will characterize molecular glue spots, elucidate molecular glue-mediated associations and uncover the reason for protein co-localization in cells.

The overarching goal of the work is to computationally guide molecular glue design and protein engineering to achieve desired functions. The work has application to cell biology studies and pharmaceutical development, as molecular glues recover lost protein regulation in cells. The project will also contribute to the training of graduate and undergraduate students.

A summer workshop will be organized to train students from local community colleges, universities and high schools.

Cells may use a molecular glue to form a ternary complex, thereby strengthening protein-protein associations. However, the mechanisms of glue-mediated ternary complex formation and how protein oligomerization enhances the overall function of protein complexes are not well understood. The project combines multi-level simulations and experimental collaboration to investigate the mechanisms of glue-enhanced protein-protein associations and the effects of protein oligomerization on the kinetic enhancement of protein function.

The design of molecular glues is informed by the mechanisms of ternary complex formation. The project explores novel ideas and incorporates results from experiments, molecular dynamics (MD), Brownian dynamics (BD) simulations, and deep learning (DL) to understand molecular glues and co-localization effects in molecular binding. The findings promise new insights into molecular glues, glue spots, and protein co-localization that will assist molecular design.

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.