Allostery and spatial organization in glycolysis: the role of phosphofructokinase 1

Glycolysis, a crucial metabolic pathway, is subjected to extensive regulation, the disturbances of which have been linked with disease. The enzyme phosphofructokinase 1 (PFK1) forms a key hotspot controlling the flux through the pathway. However, the mechanistic understanding of this regulation, which has been suggested to involve localized formation of dynamic enzyme assemblies, is still lacking. The aim of this project is to provide detailed microscopic insights into the mechanisms underlying PFK1 function and its isoform-specific regulation. To achieve this aim, we will perform molecular simulations of PFK1 and its assemblies. These simulations, which will range from the fully atomistic to an ultra-coarse-grained level, will help elucidate the mechanistic origins of the allosteric regulation of the enzyme and suggest new ways of controlling the formation of its dynamic assemblies. The work will be an important step in developing a comprehensive theoretical model of glycolysis and its dynamic intracellular organization and regulation.