Analytic models for mechanotransduction: Gating a mechanosensitive channel

Abstract

Analytic estimates for the forces and free energy generated by bilayer deformation reveal a compelling and intuitive model for MscL channel gating analogous to the nucleation of a second phase. We argue that the competition between hydrophobic mismatch and tension results in a surprisingly rich story that can provide both a quantitative comparison with measurements of opening tension for MscL when reconstituted in bilayers of different thickness, and qualitative insights into the function of the MscL channel and other transmembrane proteins.T he mechanosensitive channel (MscL) is a compelling example of the interaction between a protein and the surrounding bilayer membrane. The channel is gated mechanically by membrane tension and is thought to function as an emergency relief valve in bacteria (1). MscL is a member of a growing class of proteins that have been determined to be mechanosensitive (2, 3). The dependence of the conductance on membrane tension has been studied extensively in patch-clamp experiments (4-6). In terms of the observed conductance, these studies have revealed that the channel is very nearly a two-state system. MscL spends the vast majority of its life in either a closed state (C) or an open state (O) characterized by a discrete conductance. When the bilayer tension is small, the protein is exclusively in the closed configuration. As the tension grows, the open state becomes ever more prevalent, until it dominates at high tension. The simplest structural interpretation of this conductance data is to assume that each discrete conductance corresponds to a well defined channel conformation. This assumption seems to be compatible with the conductance data. Patch-clamp experiments have also revealed that at least three additional discrete, intermediate conductance levels exist (4), suggesting three additional short-lived substates (S1-S3). Rees and coworkers (7) have solved the structure for one conformation that appears to be the open state (6, 7) by using x-ray crystallography. MscL has also been trapped in the open state (6,8). Betanzos et al. (8) have probed the open-state structure by using disulfide crosslinking, while Perozo et al. (6) have used electron paramagnetic resonance spectroscopy (EPRS) and site-directed spin labeling (SDSL) to deduce its geometry. Sukharev et al. (9) have also proposed an open-state conformation based on structural considerations.The conformational landscape of the MscL channel is extremely complex, depending on a huge number of microscopic degrees of freedom that are analytically intractable. Even from the standpoint of numerical calculations, this number is still very large (10). As an alternative to a detailed microscopic picture of MscL, we consider a simplified free-energy function where we divide the free energy of the system into two contributions, namely,where G P is the free energy associated with the conformation of the protein and G M is the deformation free energy from the bulk of the bilayer (11). In general, these two terms are coupled. The conf...

Gating of a mechanosensitive channel due to cellular flows

“…Although the modeling results in ref. 20 were compared only with experimental data of bacterial MS channels, we expect the underlying physics to be a general mechanical feature of MS channels in different mechanosensitive systems. The previous model assumes a planar lipid bilayer membrane with a constant tension and has also been extended to the interaction between two MS channels (29).…”

“…Such idealized model systems for gating of MS channels in cells are suitable for elucidating the detailed gating mechanism coupled with the membrane dynamics, which is intrinsically multiscale both in space and in time. Coarse-grained MD simulations of such systems would take too long, given the current computational power, and thus are not practical.Motivated by the recent success of continuum modeling of MS channels (13,20,23), in this paper we propose a multiscale continuum model to study the gating of a single MS channel by tension in a membrane exposed to fluid stress. In particular, as highlighted in Fig.…”

“…Motivated by the recent success of continuum modeling of MS channels (13,20,23), in this paper we propose a multiscale continuum model to study the gating of a single MS channel by tension in a membrane exposed to fluid stress. In particular, as highlighted in Fig.…”

“…Their gating mechanisms have been investigated by experiments (18), continuum modeling (20,21), and molecular dynamics (MD) simulations (22). By exerting an unphysiologically large load onto a membrane patch with a single SA channel in the center, MD simulations show that a SA channel (several nanometers in size) responds to membrane tension within a few nanoseconds (22).…”

Bacterial Mechanosensitive Channels: Models for Studying Mechanosensory Transduction

“…Furthermore, simulations of MscL in lipids of different chain lengths suggest that membrane thinning causes structural changes in the protein to avoid a hydrophobic mismatch between protein and the lipid bilayer (39,46). Analytical approaches (156,157), coarsegrained MD (118), and free energy simulations (131) confirmed the importance of hydrophobic matching, lateral pressure profiles, and mechanical forces in the bilayer on the mechanism and energy profile of MscL gating.…”