The N-Terminal Domain Acts as an Anchor during the Gating Cycle of MscL

Abstract

This study utilizes a finite element (FE) model to probe the gating mechanism of the mechanosensitive channel of large conductance (MscL). When compared to molecular dynamics simulations, FE computations are generally more applicable due to their much longer simulation times as well as larger size scales. Herein we use an FE model of MscL, which has been developed as an initial template to provide not only information about the gating cycle of this channel but also to provide a structural framework for a mechanistic understanding of the gating of other MS channels at the continuum level. The FE model, unlike molecular dynamics simulations, utilized membrane tension corresponding to midpoint activation of MscL close to that seen in patch-clamp experiments (<12 mN/m). For MscL in the open state, our model indicates that the N-terminus and TM1 of each subunit become aligned to form a single helix. Previous mutagenic work suggests that the N-terminus of MscL, which connects the TM1 helix to the lipid bilayer at an angle of ∼95° in the closed state, is imperative for mechanosensation of the channel. In agreement with experimental data, deletion of the N-terminal domain from our model increases the tensional force required for the full opening of MscL. Moreover, we observed that during gating, the channel gate moves from the inner leaflet region towards the bilayer midplane as the membrane thins. Since we do not see this upward movement of the gate when the N-terminal is removed from our model this further implies that N-terminal region acts as an anchor in the gating process of MscL.Supported by the University International Postgraduate Award (UIPA) to N.B. and APP1079398 grant from NHMRC to B.M.