Molecular Dynamics Study of MscL Interactions with a Curved Lipid Bilayer

Abstract

Mechanosensitivity is a ubiquitous sensory mechanism found in living organisms. The simplest known mechanotransducing mechanism is found in bacteria in the form of the mechanosensitive membrane channel of large conductance, MscL. This channel has been studied extensively using a variety of methods at a functional and structural level. The channel is gated by membrane tension in the lipid bilayer alone. It serves as a safety valve protecting bacterial cells against hypoosmotic shock. MscL of Escherichia coli embedded in bilayers composed of asymmetric amounts of single-tailed and double-tailed lipids has been shown to gate spontaneously, even in the absence of membrane tension. To gain insight into the effect of the lipid membrane composition and geometry on MscL structure, a fully solvated, all-atom model of MscL in a stress-free curved bilayer composed of double- and single-tailed lipids was studied using a 9.5-ns molecular dynamics simulation. The bilayer was modeled as a domed structure accommodating the asymmetric composition of the monolayers. During the course of the simulation a spontaneous restructuring of the periplasmic loops occurred, leading to interactions between one of the loops and phospholipid headgroups. Previous experimental studies of the role of the loops agree with the observation that opening starts with a restructuring of the periplasmic loop, suggesting an effect of the curved bilayer. Because of limited resources, only one simulation of the large system was performed. However, the results obtained suggest that through the geometry and composition of the bilayer the protein structure can be affected even on short timescales.

The gating mechanism of the bacterial mechanosensitive channel MscL revealed by molecular dynamics simulations

“…11 The S1 in the revised version has a helical structure running parallel to the cytoplasmic membrane surface instead of In order to examine the structural changes during the opening of MscL in atomic detail, molecular simulations, including all atom and coarse-grained models, have been conducted. [20][21][22][23][24][25][26][27][28] The first problem to simulate channel opening is how to apply forces to a modeled MscL. One method employed force tethered to particular AAs or whole-channel proteins.…”

“…Another method is to generate stress in the MscL-embedded membrane by modifying the bilayer structure. 25,26 This method is based on the findings that pressure distribution in the membrane varies with the type of the membrane and that the pressure profile of the membrane affects the channel gating, 22 however, it could not induce MscL opening within the simulation period, 25 or only revealed that how MscL adapt to a thinner membrane. 26 Therefore, it is critically important to develop a stimulation method that can mimic the membrane stretching, which is used in most experiments to stimulate MscL.…”

Bacterial Mechanosensitive Channels: Models for Studying Mechanosensory Transduction

“…Its function is also not known, although it has been proposed that the loop behaves as a molecular spring, resisting the channel opening (1). This notion has found support from results of mutagenesis (100), EPR spectroscopic (102,149), and MD studies (40,103). Nevertheless, further experimental and modeling studies are needed to fully establish the role of this structural domain of MscL.…”

“…The other global determinant, bilayer curvature and/or transbilayer pressure profile, has been established as the major factor regulating MscL and MscS structural conformations. With regard to specific interactions of the MscL and MscS structural components with surrounding phospholipids, several studies have suggested that the periplasmic and cytoplasmic regions are critical for these interactions (103,111,149,163,166).…”

“…To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars the protein in a particular direction, and the use of large forces or tension can distort the protein. This can be avoided by simulating the protein in a curved lipid bilayer (103). Another alternative is to incorporate structural data from experiments into MD simulations, as in a recent study by Corry and colleagues in which experimentally derived distances from 80 FRET-derived distance constraints and 640 EPR constraints were used to model the open pore of MscL (31).…”