Abstract
During the final step of the bacteriophage infection cycle, the cytoplasmic membrane of host cells is disrupted by small membrane proteins called holins. The function of holins in cell lysis is carried out by forming a highly ordered structure called lethal lesion, in which the accumulation of holins in the cytoplasmic membrane leads to the sudden opening of a hole in the middle of this oligomer. Previous studies showed that dimerization of holins is a necessary step to induce their higher order assembly. However, the molecular mechanism underlying the holin-mediated lesion formation is not well understood. In order to elucidate the functions of holin, we first computationally constructed a structural model for our testing system: the holin S105 from bacteriophage lambda. All atom molecular dynamic simulations were further applied to refine its structure and study its dynamics as well as interaction in lipid bilayer. Additional simulations on association between two holins provide supportive evidence to the argument that the C-terminal region of holin plays a critical role in regulating the dimerization. In detail, we found that the adhesion of specific nonpolar residues in transmembrane domain 3 (TMD3) in a polar environment serves as the driven force of dimerization. Our study therefore brings insights to the design of binding interfaces between holins, which can be potentially used to modulate the dynamics of lesion formation.
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Acknowledgements
This work is supported by the National Institutes of Health under Grant Numbers R01GM120238 and R01GM122804. This work is also partially supported by a Start-up Grant from Albert Einstein College of Medicine. Computational support is provided by Albert Einstein College of Medicine High Performance Computing Center, and the NSF through XSEDE resources under Grant Number TG-MCB200002.
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Zhou, B., Wu, Y. & Su, Z. Computational Simulation of Holin S105 in Membrane Bilayer and Its Dimerization Through a Helix-Turn-Helix Motif. J Membrane Biol 254, 397–407 (2021). https://doi.org/10.1007/s00232-021-00187-w
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DOI: https://doi.org/10.1007/s00232-021-00187-w