The N-Terminal Domain of Bacterial Mechanosensitive MscL Acts as a Mechanosensor: Molecular Dynamics Study

The bacterial mechanosensitive channel MscL is constituted of homopentamer of a subunit with two transmembrane inner and outer (TM1, TM2) α-helices, and its 3D structure of the closed state has been resolved. The major issue of MscL is to understand the gating mechanism driven by tension in the membrane. To address this question, molecular dynamics (MD) studies have been performed, however, as they do not include MscL-lipid interactions, it remains unclear which amino acids sense membrane tension and how the sensed force induces channel opening. Thus we performed MD simulations for the opening of MscL embedded in the lipid bilayer. Among amino acids in TM2 facing the bilayer, Phe78 showed exceptionally strong interaction with lipids. Upon membrane stretch, Phe78 was dragged by lipids, leading to an opening of MscL. Thus Phe78 was concluded to be the major tension sensor. Neighboring TM1s cross and interact with each other near the cytoplasmic side through hydrophobic interaction between Leu19-Val23 in one TM1 and Gly22 in the neighboring TM1, forming the most constricted hydrophobic part of the pore called gate. Upon membrane stretch, the helices are dragged by lipids at Phe78 and tilted, accompanied by the outward sliding of the crossings, leading to expanding of the gate. In this study, we newly modeled the Eco-MscL with the N-terminal (S1) helices running parallel to the cytoplasmic membrane instead of forming the tight bundle proposed previously and determined the role of the S1 helices in channel opening. As a result, the newly modeled MscL opened faster than the previous one. Furthermore, some amino acids in the S1 interact with lipids rigidly, suggesting that the S1 acts as a mechanosensor to transmit force for accelerating the gate opening.