Abstract
Negative cooperativity is a phenomenon in which the binding of a first ligand or substrate molecule 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 binding events. Negative cooperativity turns the binding curve more graded and cannot be distinguished from two independent and different binding events based on equilibrium measurements only. The need of kinetic data for this purpose was already reported. Here, we study the binding response as a function of the amount of ligand, at different times, from very early times since ligand is added and until equilibrium is reached. Over those binding curves measured at different times, we compute the dynamic range: the fold change required in input to elicit a change from 10 to 90% of maximum output, finding that it evolves in time differently and 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 adds understanding on the molecular mechanisms at play, and thus, is a valuable tool. The methods developed in this article were tested both with simulated and experimental data, showing to be robust to noise and experimental constraints.
Highlights
Cells detect input signaling molecules using receptors, proteins usually located on the cell surface embedded in the plasma membrane
When two successive events occur, it may make sense to know if they affect somehow each other, if the properties of the second event are modified by the occurrence of the first one
We have shown before that when a ligand-receptor system is exposed to a step-like temporal profile of ligand, the occupied receptor dose-response curve changes over time in such a way that the EC50 becomes progressively smaller with a minimum when the binding reaction reaches steady-state [21]
Summary
Cells detect input signaling molecules using receptors, proteins usually located on the cell surface embedded in the plasma membrane. Activated receptors transmit the signal to the interior of the cell through a series of downstream processes that typically lead to changes in gene expression, resulting in an appropriate output response to the input. The system’s overall input-output curve summarizes its biological characteristics and function [1]. Receptors have usually more than one binding site. Cooperativity in binding is defined as a change in the properties of a given site depending on the state (occupied or not) of the other. If the second binding is weaker once the first site is occupied, this is called negative cooperativity.
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