Discriminating between negative cooperativity and ligand binding to independent sites using pre-equilibrium properties of binding curves

ALEJANDRA C VENTURA

Santiago de Chile

Workshop; 7mo workshop Modelamiento Matemático de Sistemas Biológicos (WMMSB); 2024

Grupo de Modelamiento Matemático de Sistemas Biológicos, Universidad Tecnológica Metropolitana

Negative cooperativity is a phenomenon in which the binding of a first ligand or substratemolecule decreases the rate of subsequent binding. This definition is not exclusive to ligand-receptor binding, it holds whenever two or more molecules undergo two successive bindingevents. Negative cooperativity turns the binding curve more graded and cannot be distinguishedfrom two independent and different binding events based on equilibrium measurements only.We study the binding response as a function of the amount of ligand, at different times, fromvery early times since ligand is added and until equilibrium is reached. Over those binding curvesmeasured at different times, we compute the dynamic range: the fold change required in inputto elicit a change from 10 to 90% of maximum output, finding that it evolves in time differentlyand controlled by different parameters in the two situations that are identical in equilibrium.Deciphering which is the microscopic model that leads to a given binding curve addsunderstanding on the molecular mechanisms at play, and thus, is a valuable tool. The methodsdeveloped in our work were tested both with simulated and experimental data, showing to berobust to noise and experimental constraints.