Abstract
A new mechanism of allostery in proteins, based on charge rather than structure, is reported. We demonstrate that dynamic redistribution of charge within a protein can control its function and affect its interaction with a binding partner. In particular, the association of an antibody with its target protein antigen is studied. Dynamic charge shifting within the antibody during its interaction with the antigen is enabled by its binding to a metallic surface that serves as a source for electrons. The kinetics of antibody–antigen association are enhanced when charge redistribution is allowed, even though charge injection happens at a position far from the antigen binding site. This observation points to charge-reorganization allostery, which should be operative in addition or parallel to other mechanisms of allostery, and may explain some current observations on protein interactions.
Highlights
There is a well-established relation between structure and function in proteins, which is supported by multiple experimental and theoretical tools
Protein−protein interactions (PPA) are ubiquitous in living systems and are often subject to allosteric modulation. It has been known for a long time that PPA may involve electrostatic interactions between charged groups located at the interaction site, and may modify the diffusion-limited association rate in a multiplicative manner.[8−11] Theoretical analysis of PPA often takes into account the static distribution of charges on the surfaces of the proteins, which is related to the location of charged amino acid residues.[11]
This leads to a new allosteric mechanism, charge-reorganization allostery, which must accompany any situation in which a protein is interacts with another species or is exposed to an electric field within the biological environment
Summary
There is a well-established relation between structure and function in proteins, which is supported by multiple experimental and theoretical tools. An important tenet of the structure−function paradigm is the allosteric effect,[1] i.e. the modulation of the function of a protein through the binding of a small molecule or of another protein at a location far away from the active site.[2−4] Classical allosteric mechanisms involve protein conformational changes,[5,6] and more recently it has been shown that changes in conformational dynamics may lead to allosteric effects.[7] Protein−protein interactions (PPA) are ubiquitous in living systems and are often subject to allosteric modulation It has been known for a long time that PPA may involve electrostatic interactions between charged groups located at the interaction site, and may modify the diffusion-limited association rate in a multiplicative manner.[8−11] Theoretical analysis of PPA often takes into account the static distribution of charges on the surfaces of the proteins, which is related to the location of charged amino acid residues.[11] In this work, it is found that the electrostatic effect can be nonlocal and can be controlled by the ability of the protein to withdraw charge at sites remote to its reaction site and redistribute these charges throughout its structure. This leads to a new allosteric mechanism, charge-reorganization allostery, which must accompany any situation in which a protein is interacts with another species or is exposed to an electric field within the biological environment
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