Spatiotemporal dynamics of self-organizing protein complexes through a computational lens

Protein complexes are organized structures composed of hundreds to thousands of copies of one to a few types of proteins. Nature has evolved these protein complexes as a means to create biological machines with diverse cellular functions, including those critical to human health. To date, the organizing principles for protein complexes have focused on hierarchically-evolving spatial organization and the challenge is to extend this framework towards inherently dynamic complexes with structures and functions that vary in time, often in response to environmental signals. The goal of my research program and this MIRA proposal is to investigate the structure-dynamics-function relationships that regulate the biogenesis of protein complexes with a current emphasis on proteinaceous organelles and envelopes. Here, we specifically target two families of bacterial proteins – S-layers and microcompartments – that will serve as excellent model systems to further our fundamental understanding of the spatiotemporal organization of protein complexes. Our work will address two challenging paradigms: (i) complexity due to large combinatorial space (from many types of interacting proteins) and (ii) complexity due to large conformational space (from many protein domains bound by flexible linkers). Our approach is to develop and to apply new computational models, simulation strategies, and analysis frameworks that will make the study of these systems tractable. Our findings will have substantive impact on the broader understanding of bacterial biogenesis, and in the long term, can be applied to develop new therapeutics that target pathogenic bacteria, adapted to study dynamic protein complexes relevant to disease progression, and repurposed to aid synthetic biology efforts for protein-based biotechnology. Project Number: 5R35GM157192-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Alexander Pak | Institution: COLORADO SCHOOL OF MINES, GOLDEN, CO | Award Amount: $335,830 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award B Study Section[MRAB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11396268