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Molecular dynamics study on protein-water interplay in the mechanogating of the bacterial mechanosensitive channel MscL.

Sawada Y, Sokabe M - Eur. Biophys. J. (2015)

Bottom Line: The gating behaviors in this model and the normal MscL model, in which water movements are unrestrained, are compared.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Time courses of changes in the pore radius and the number of water molecules at the gate of MscL in response to tension increase. Black and red colored curves denote changes in the pore radius at the most constricted portion of the pore with unrestrained and restrained water molecules, respectively. Blue colored curve depicts changes in the number of water molecules in the gate space formed between Leu19 and Val23 of TM1 helices in the unrestrained water model, while the number of water molecules was kept at zero (not shown) in the restrained water model. A tension increase was applied at time zero
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Fig4: Time courses of changes in the pore radius and the number of water molecules at the gate of MscL in response to tension increase. Black and red colored curves denote changes in the pore radius at the most constricted portion of the pore with unrestrained and restrained water molecules, respectively. Blue colored curve depicts changes in the number of water molecules in the gate space formed between Leu19 and Val23 of TM1 helices in the unrestrained water model, while the number of water molecules was kept at zero (not shown) in the restrained water model. A tension increase was applied at time zero

Mentions: When the membrane tension increased in the normal MscL model with unrestrained water, transmembrane helices (TM1 and TM2) were gradually tilted to the membrane plane, accompanied by outward sliding of the crossings between TM1 helices. By this mechanism, the gate expanded (Fig. 3a, b). Almost identical expanding behavior occurs in the MscL model with five bundled S1 helices in the cytoplasmic space (Chang et al. 1998); this model was adopted in our previous study (Sawada et al. 2012). As TM1 helices slide each other in the radial direction, the partner of the Leu19–Val23 pocket will shift from Gly22 to Gly26 (Fig. 1c). Further sliding leads to the most expanded state of the gate (radius = 5.4 Å in our simulations; Fig. 4). At approximately 3.5 ns of simulation, although the gate was still narrow with a radius of 1.7 Å [Figs. 3b(ii), 4], most of its hydrophobic surface had become hydrated [Fig. 3c(ii)]. Hydration was initiated by a single water molecule accessing the backbone carbonyl oxygen atom of Leu19 [Fig. 3d(ii)]. More precisely, the dragging force on TM1 arising from the tensile force exerted on Phe78 generated a kinking force near Leu19, which eventually broke the hydrogen bond between Leu19 and Val23. Consequently, the backbone carbonyl oxygen atom of Leu19 was exposed to the lumen of the pore, allowing interactions with water molecules, although the upper and lower vapor–water interfaces remained intact. Before complete merging of the upper and lower water phases, a single string of water molecules was formed across the constriction [Fig. 3c(ii)]. Then most of the hydrophobic surface of the gate came to be covered with water molecules, while the pore gradually expanded until the gate became completely wetted [Fig. 3c(iii)]. As shown in Fig. 4, the gate expanded slowly until 3.5 ns of simulation with few water molecules in the gate, but after 3.5 ns, it became considerably expanded, while the number of water molecules occupying the gate increased dramatically.Fig. 4


Molecular dynamics study on protein-water interplay in the mechanogating of the bacterial mechanosensitive channel MscL.

Sawada Y, Sokabe M - Eur. Biophys. J. (2015)

Time courses of changes in the pore radius and the number of water molecules at the gate of MscL in response to tension increase. Black and red colored curves denote changes in the pore radius at the most constricted portion of the pore with unrestrained and restrained water molecules, respectively. Blue colored curve depicts changes in the number of water molecules in the gate space formed between Leu19 and Val23 of TM1 helices in the unrestrained water model, while the number of water molecules was kept at zero (not shown) in the restrained water model. A tension increase was applied at time zero
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562998&req=5

Fig4: Time courses of changes in the pore radius and the number of water molecules at the gate of MscL in response to tension increase. Black and red colored curves denote changes in the pore radius at the most constricted portion of the pore with unrestrained and restrained water molecules, respectively. Blue colored curve depicts changes in the number of water molecules in the gate space formed between Leu19 and Val23 of TM1 helices in the unrestrained water model, while the number of water molecules was kept at zero (not shown) in the restrained water model. A tension increase was applied at time zero
Mentions: When the membrane tension increased in the normal MscL model with unrestrained water, transmembrane helices (TM1 and TM2) were gradually tilted to the membrane plane, accompanied by outward sliding of the crossings between TM1 helices. By this mechanism, the gate expanded (Fig. 3a, b). Almost identical expanding behavior occurs in the MscL model with five bundled S1 helices in the cytoplasmic space (Chang et al. 1998); this model was adopted in our previous study (Sawada et al. 2012). As TM1 helices slide each other in the radial direction, the partner of the Leu19–Val23 pocket will shift from Gly22 to Gly26 (Fig. 1c). Further sliding leads to the most expanded state of the gate (radius = 5.4 Å in our simulations; Fig. 4). At approximately 3.5 ns of simulation, although the gate was still narrow with a radius of 1.7 Å [Figs. 3b(ii), 4], most of its hydrophobic surface had become hydrated [Fig. 3c(ii)]. Hydration was initiated by a single water molecule accessing the backbone carbonyl oxygen atom of Leu19 [Fig. 3d(ii)]. More precisely, the dragging force on TM1 arising from the tensile force exerted on Phe78 generated a kinking force near Leu19, which eventually broke the hydrogen bond between Leu19 and Val23. Consequently, the backbone carbonyl oxygen atom of Leu19 was exposed to the lumen of the pore, allowing interactions with water molecules, although the upper and lower vapor–water interfaces remained intact. Before complete merging of the upper and lower water phases, a single string of water molecules was formed across the constriction [Fig. 3c(ii)]. Then most of the hydrophobic surface of the gate came to be covered with water molecules, while the pore gradually expanded until the gate became completely wetted [Fig. 3c(iii)]. As shown in Fig. 4, the gate expanded slowly until 3.5 ns of simulation with few water molecules in the gate, but after 3.5 ns, it became considerably expanded, while the number of water molecules occupying the gate increased dramatically.Fig. 4

Bottom Line: The gating behaviors in this model and the normal MscL model, in which water movements are unrestrained, are compared.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

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.

No MeSH data available.


Related in: MedlinePlus