Hydration properties of mechanosensitive channel pores define the energetics of gating

Department of Biology, University of Maryland, College Park, MD 20742, USA.
Journal of Physics Condensed Matter (Impact Factor: 2.35). 11/2010; 22(45):454120. DOI: 10.1088/0953-8984/22/45/454120
Source: PubMed


Opening of ion channels directly by tension in the surrounding membrane appears to be the most ancient and simple mechanism of gating. Bacterial mechanosensitive channels MscL and MscS are the best-studied tension-gated nanopores, yet the key physical factors that define their gating are still hotly debated. Here we present estimations, simulations and experimental results showing that hydration of the pore might be one of the major parameters defining the thermodynamics and kinetics of mechanosensitive channel gating. We associate closing of channel pores with complete dehydration of the hydrophobic gate (occlusion by 'vapor lock') and formation of two water-vapor interfaces above and below the constriction. The opening path is the expansion of these interfaces, ultimately leading to wetting of the hydrophobic pore, which does not appear to be the exact reverse of the closing path, thus producing hysteresis. We discuss specifically the role of polar groups (glycines) buried in narrow closed conformations but exposed in the open states that change the wetting characteristics of the pore lining and stabilize conductive states of the channels.

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    • "Anishkin et al. (2010) calculated the hydration energy for the MscL gate opening and discussed the importance of Gly22 and Gly26. Both amino acids are buried in the closed conformation but exposed to the lumen side in the open state, which would change the wetting characteristics of the pore (Anishkin et al. 2010). The hydrophobic nature of the MscL gate interrupts the continuous water column through the channel by forming a vapor plug between Leu19 and Val23. "
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    ABSTRACT: One of the goals of mechanosensitive channel (MSC) studies is to understand the underlying molecular and biophysical mechanisms of the mechano-gating process from force sensing to gate opening. We focus on the latter process and investigate the role of water in the bacterial MSC MscL, which is activated by membrane tension. We analyze the interplay between water and the gate-constituting amino acids, Leu19-Gly26, through molecular dynamics simulations. To highlight the role of water, specifically hydration of the gate, in MscL gating, we restrain lateral movements of the water molecules along the water-vapor interfaces at the top and bottom of the vapor bubble, plugging the closed gate. The gating behaviors in this model and the normal MscL model, in which water movements are unrestrained, are compared. In the normal model, increased membrane tension breaks the hydrogen bond between Leu19 and Val 23 of the inner helix, exposing the backbone carbonyl oxygen of Leu19 to the water-accessible lumen side of the gate. Associated with this activity, water comes to access the vapor region and stably interacts with the carbonyl oxygen to induce a dewetting to wetting transition that facilitates gate expansion toward channel opening. By contrast, in the water-restrained model, carbonyl oxygen is also exposed, but no further conformational changes occur at the gate. This suggests that gate opening relies on a conformational change initiated by wetting. The penetrated water weakens the hydrophobic interaction between neighboring transmembrane inner helices called the "hydrophobic lock" by wedging into the space between their interacting portions.
    Biophysics of Structure and Mechanism 08/2015; 44(7). DOI:10.1007/s00249-015-1065-2 · 2.22 Impact Factor
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    • "Computationally, improved water–water and water– protein interaction parameters are needed to describe the relative wettability of transmembrane pores (see discussion in Ref. [19]). Polarizable force fields and better descriptions of transmembrane voltage are also needed [76] [77]. "
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    ABSTRACT: Biological ion channels are nanoscale transmembrane pores. When water and ions are enclosed within the narrow confines of a sub-nanometer hydrophobic pore, they exhibit behavior not evident from macroscopic descriptions. At this nanoscopic level, the unfavorable interaction between the lining of a hydrophobic pore and water may lead to stochastic liquid-vapor transitions. These transient vapor states are 'dewetted' i.e. effectively devoid of water molecules within all, or part of the pore, thus leading to an energetic barrier to ion conduction. This process, termed 'hydrophobic gating', was first observed in molecular dynamics simulations of model nanopores, where the principles underlying hydrophobic gating (i.e. changes in diameter, polarity, or transmembrane voltage) have now been extensively validated. Computational, structural and functional studies now indicate that biological ion channels may also exploit hydrophobic gating to regulate ion flow within their pores. Here we review the evidence for this process, and propose that this unusual behavior of water represents an increasingly important element in understanding the relationship between ion channel structure and function.
    Journal of Molecular Biology 08/2014; 427(1). DOI:10.1016/j.jmb.2014.07.030 · 4.33 Impact Factor
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    • "The average activation/inactivation midpoint ratio was 0.89 ± 0.14, whereas the average activation/inactivation threshold ratio was 1.48 ± 0.50 (n = 7 patches). This mild hysteresis, wherein MscS channels required lower tension to open than to close, and opened at a faster rate, is similar to that reported previously (Sukharev et al., 2007; Anishkin et al., 2010; Belyy et al., 2010a). We observed more prominent hysteresis in about half of recordings made with smaller (BN 5) pipettes. "
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    ABSTRACT: We have successfully expressed and characterized mechanosensitive channel of small conductance (MscS) from Escherichia coli in oocytes of the African clawed frog, Xenopus laevis. MscS expressed in oocytes has the same single-channel conductance and voltage dependence as the channel in its native environment. Two hallmarks of MscS activity, the presence of conducting substates at high potentials and reversible adaptation to a sustained stimulus, are also exhibited by oocyte-expressed MscS. In addition to its ease of use, the oocyte system allows the user to work with relatively large patches, which could be an advantage for the visualization of membrane deformation. Furthermore, MscS can now be compared directly to its eukaryotic homologues or to other mechanosensitive channels that are not easily studied in E. coli.
    The Journal of General Physiology 11/2011; 138(6):641-9. DOI:10.1085/jgp.201110723 · 4.79 Impact Factor
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