Biophys J, June 1998, p. 2889-2902, Vol. 74, No. 6

Electromechanical Coupling Model of Gating the Large Mechanosensitive Ion Channel (MscL) of Escherichia coli by Mechanical Force

Department of Pharmacology, University of Western Australia, Nedlands WA 6907, Australia

We have developed a theoretical electromechanical coupling (EMC) model of gating of the large-conductance mechanosensitive ion channel (MscL). The model presents the first attempt to explain the pressure-dependent transitions between the closed and open channel conformations on a molecular level by assuming 1) a homohexameric structural model of the channel, 2) electrostatic interactions between various domains of the homohexamer, 3) structural flexibility of the N-terminal portion of the monomer, and 4) mechanically and electrostatically induced displacement of the N-terminal domain relative to other structural domains of the protein. In the EMC model, 12 membrane-spanning -helices (six each of the M1 and M2 transmembrane domains of the MscL monomer), are envisaged to line the channel pore with a diameter of 40 Å, whereas the N- and C-termini are oriented toward each other inside the pore when the channel is closed. The model proposes that stretching the membrane bilayer by mechanical force causes the monomers to be pulled away from and slightly tilted toward each other. This relative movement of -helices could serve as a trigger to initiate a "swing-like" motion of the N-terminus around the glycine residue G14 that may act as a pivot. The analysis of the attractive and repulsive coulomb forces between all domains of the channel homohexamer suggested that an inclination angle of ~3.0°-4.1° between the oppositely oriented channel monomers should suffice for the N-terminus to turn away from other domains causing the channel to open. According to the EMC model the minimal free energy change, G, that could initiate the opening of the channel was 2 kT. Also, the model predicted that the negative pressure required for channel open probability, P_o = 0.5, should be between 50 and 80 mmHg. These values were in a good agreement with the experimentally estimated pressures of 60-70 mmHg obtained with the MscL reconstituted in liposomes. Furthermore, consistent with a notion that the N-terminus may present a mechanosensitive structural element providing a mechanism to open the MscL by mechanical force, the model provides a simple explanation for the variations in pressure sensitivity observed with several MscL mutants having either deletions or substitutions in N- or C-terminus, or site-directed mutations in the S2-S3 loop.

Biophys J, June 1998, p. 2889-2902, Vol. 74, No. 6
© 1998 by the Biophysical Society   0006-3495/98/06/2889/14  $2.00

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