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Thresholds and ultrasensitivity from negative cooperativity.

ABSTRACT: Negative cooperativity is a phenomenon in which the binding of one or more molecules of a ligand to a multimeric receptor makes it more difficult for subsequent ligand molecules to bind. Negative cooperativity can make a multimeric receptor's response more graded than it would otherwise be. However, through theory and experimental results, we show that if the ligand binds the receptor with high affinity and can be appreciably depleted by receptor binding, then negative cooperativity produces a qualitatively different type of response: a highly ultrasensitive response with a pronounced threshold. Because ultrasensitivity and thresholds are important for generating various complex systems-level behaviors, including bistability and oscillations, negative cooperativity may be an important ingredient in many types of biological responses.

SUBMITTER: Ha SH

PROVIDER: S-EPMC5184821 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Thresholds and ultrasensitivity from negative cooperativity.

Ha S H SH Ferrell J E JE

Science (New York, N.Y.) 20160512 6288

Negative cooperativity is a phenomenon in which the binding of one or more molecules of a ligand to a multimeric receptor makes it more difficult for subsequent ligand molecules to bind. Negative cooperativity can make a multimeric receptor's response more graded than it would otherwise be. However, through theory and experimental results, we show that if the ligand binds the receptor with high affinity and can be appreciably depleted by receptor binding, then negative cooperativity produces a q ...[more]

PMID: 27174675

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Project description:Networks of H-bonds can show non-additive behaviour, where the strength of one interaction perturbs another. The magnitude of such cooperative effects can be quantified by measuring the effect of the presence of an intramolecular H-bond at one site on a molecule on the association constant for formation of an intermolecular H-bond at another site. This approach has been used to quantify the cooperativity associated with the interaction of a primary amine with two H-bond acceptors. A series of compounds that have an intramolecular H-bond between an aniline NH2 group and a pyridine nitrogen were prepared, using polarising substituents on the pyridine ring to vary the strength of the intramolecular H-bond. The presence of the intramolecular interaction was confirmed by X-ray crystallography in the solid state and NMR spectroscopy in n-octane solution. UV-vis absorption titrations were used to measure the association constants for formation of an intermolecular H-bond with tri-n-butyl phosphine oxide in n-octane. Electron-donating substituents on the pyridine ring, which increase the strength of the intramolecular H-bond, were found to decrease the strength of the intermolecular H-bond between the aniline and the phosphine oxide. The results were used to determine the H-bond donor parameters for the anilines, α, and there is a linear relationship between the values of α and the H-bond acceptor parameter of the pyridine group involved in the intramolecular H-bond, β. The slope of this relationship was used to determine the cooperativity parameter (κ = -0.10), which quantifies the negative allosteric cooperativity between the two H-bonding interactions. Calculated molecular electrostatic potential surfaces of the anilines quantitatively reproduce the experimental result, which suggests that effects are electrostatic in origin, either due to polarisation of the NH bonds or due to secondary electrostatic interactions between the two H-bond acceptors.

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Thresholds and ultrasensitivity from negative cooperativity.

Publications

Thresholds and ultrasensitivity from negative cooperativity.

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