Why Antiholins? Thermodynamic and Kinetic Arguments to Explain the Robustness of Bacteriophage Cell Lysis

Cell lysis is one of the most common biological processes in which viruses infect and destroy bacterial cells. It is accomplished by viruses stimulating cell hosts to produce holin proteins that assemble in cellular membranes and break them at specific times. One of the most surprising observations in cell lysis is that antiholin proteins that inhibit membrane permeabilization are also produced. It remains unclear what is the function of antiholins if they do not trigger the membrane lesions. We propose a novel theoretical idea to explain the role of antiholins. We hypothesize that antiholin-holin interactions support the robustness of cell lysis when the external conditions fluctuate. To test this idea, we developed a minimal theoretical model that allows us to investigate the thermodynamic and kinetic properties of the system explicitly. By comparing a two-state system (without antiholins) and a three-state system (with antiholins), we examined how temperature and interaction energies influence the formation of holin dimers, a key determinant of lysis timing. Our results reveal that without antiholins, increasing temperature always decreases holin dimerization, leading to a reduction in the probability and slower rates of cell lysis. However, the presence of antiholins eliminates these effects, increasing the probability and rates of cell lysis. It is argued that this results from a compensatory mechanism that effectively buffers holin dimers from these environmental variations. These findings suggest that antiholins are stabilizing elements that ensure robust cell lysis under fluctuating physiological conditions.