Abstract
The bacterial mechanosensitive channel MscL, a small protein mainly activated by membrane tension, is a central model system to study the transduction of mechanical stimuli into chemical signals. Mutagenic studies suggest that MscL gating strongly depends on both intra-protein and interfacial lipid-protein interactions. However, there is a gap between this detailed chemical information and current mechanical models of MscL gating. Here, we investigate the MscL bilayer-protein interface through molecular dynamics simulations, and take a combined continuum-molecular approach to connect chemistry and mechanics. We quantify the effect of membrane tension on the forces acting on the surface of the channel, and identify interactions that may be critical in the force transduction between the membrane and MscL. We find that the local stress distribution on the protein surface is largely asymmetric, particularly under tension, with the cytoplasmic side showing significantly larger and more localized forces, which pull the protein radially outward. The molecular interactions that mediate this behavior arise from hydrogen bonds between the electronegative oxygens in the lipid headgroup and a cluster of positively charged lysine residues on the amphipathic S1 domain and the C-terminal end of the second trans-membrane helix. We take advantage of this strong interaction (estimated to be 10–13 kT per lipid) to actuate the channel (by applying forces on protein-bound lipids) and explore its sensitivity to the pulling magnitude and direction. We conclude by highlighting the simple motif that confers MscL with strong anchoring to the bilayer, and its presence in various integral membrane proteins including the human mechanosensitive channel K2P1 and bovine rhodopsin.
Highlights
Mechanosensitive (MS) proteins are responsible for the conversion between mechanical and chemical signals
We begin by analyzing the molecular dynamics (MD) results following a continuum approach that quantifies the internal stress state of the system and how tension affects the interaction between the membrane and the MS channel of large conductance (MscL) protein
We have presented a simulation approach that combines molecular characterization with a continuum mechanics analysis, which provides insight into how global physical quantities such as membrane tension affect the local behavior within the membrane-protein system
Summary
Mechanosensitive (MS) proteins are responsible for the conversion between mechanical and chemical signals. Mechanical stimuli imposed by cellular membranes on integral membrane proteins have been shown to play an important, and sometimes critical, role in their function. Such mechanical stimuli can be provided by tension, membrane thickness (through hydrophobic mismatch), spontaneous curvature, and stress distribution given by lipid composition or bilayer asymmetry [1,2,3]. Observations from a recent molecular dynamics study indicate that the interaction between lipids and hydrophobic amino acids, such as phenyl alanine, play an important role in gating [15]. The molecular surface of proteins is rugged with many features that may serve as binding sites for neighboring lipids [16]
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