The effects of external electric fields on proteins.

Proteins are highly abundant and, as a biomolecular class, have very versatile functions in living systems. Protein structures contain electrically charged residues and proteins' electrostatics are crucial for their function. Although protein activity is commonly modulated through a variety of ligands and post-translational modifications, an external electric field (EF) represents an alternative, physical approach. By exerting forces on charged and dipolar regions, EFs can reshape the energetic landscape and dynamic behavior of proteins. This approach offers a mass-free, rapidly switchable, spatially precise, non-contact, and reagent-free way to control protein conformation and function - features increasingly appealing for applications in green bioprocessing, neuromodulation, ultrafast structural biology, and in studying proteins without clearly ligandable sites. Despite the growing evidence for diverse and reversible control of proteins by EF, the mechanisms are still underexplored and applications have not yet grown to their full potential. This review focuses on molecular mechanisms and integrates the findings of the effects of external EFs on proteins from both computational simulations and experimental studies. The literature shows that the EF acts on protein charged and dipolar groups, and when the EF parameters are well tailored, the EF consequently triggers effects on protein rigid body motion, secondary structure, tertiary structure, quaternary structure and molecular conformation, ultimately leading to changes in protein interactions and function (enzymatic, ion channelling, switching, …). These effects are being utilized not only on proteins as food components but also for bionanotechnological applications, e.g. in membrane proteins for controlling their transport properties, and in structural and force-generating proteins to steer self-assembly pathways and dynamic behavior. The compiled evidence clarifies key mechanisms by which EFs influence proteins and identifies promising directions for biomedical, food-processing, and biotechnological applications.