2025 AIChE Annual Meeting

(182y) Molecular Modeling of Enzyme Co-Localization for Improved Therapeutics Biosynthesis

Authors

The growing demand for bio-manufactured therapeutics has driven interest for optimizing enzyme-catalyzed biosynthetic pathways. One such therapeutic notable for its anti-cancer properties is hesperetin, currently in limited supply due to its low abundance in natural sources. To address this challenge, a biosynthetic pathway for production of hesperetin has been developed that involves four enzymes. One of these enzymes is flavonoid 4’-O-methyltransferase (MpOMT), which converts eriodictyol to the final product hesperetin. Co-localization of multiple enzymes could potentially greatly increase enzymatic activity, increase product yield and advance enzyme scaffold design. In this study, we examine eriodictyol binding with MpOMT using molecular docking and molecular dynamics simulations in order to predict binding sites and characterize the enzyme-ligand complex. We investigate the thermodynamics of this binding process and interpret our results in the context of ultimately designing a polypeptide scaffold to co-localize each enzyme in the hesperetin biosynthesis pathway.