Blood coagulation is a network of biochemical reactions whereby dozens of proteins act collectively to initiate a rapid clotting response. Coagulation reactions are lipid-surface dependent, and this dependence is thought to help localize coagulation to the site of injury and enhance the association between reactants. Current models of coagulation fail to agree with laboratory studies under variations in lipid concentrations. Models overestimate conversion efficiencies of critical coagulation proteins and fail to capture spatial limitations of lipid surfaces. We developed a mathematical model of lipid-mediated enzyme reactions where the association rate between lipid-bound reactants is modified by an interaction probability (IP). The IP is derived by considering the fraction of the lipid surface that is occupied by any lipid-bound species, and accounts for surface crowding. We performed constrained optimization to estimate a set of intrinsic rates for the enzyme-substrate pair. Preliminary results agree with experiments and reveal a critical lipid concentration where the conversion rate of the coagulation protein is maximized, inferring that the model can describe the dilution effect where, as lipid is increased, proteins are physically separated, and reaction rates decrease. Further refinements of the model, including product inhibition due to experimental design, are also incorporated to better understand the impacts of the dilution effect in more complex reaction networks.
Modeling Enzyme Kinetics in the Presence of Lipids
Jamie Madrigal,Authors: Jamie Madrigal, Dougald Monroe, PhD, Suzanne Sindi, PhD, Karin Leiderman, PhD
2022 AWM Research Symposium