Gating of mechanosensitive channels

Mechanosensitive channels are membrane proteins that respond to various mechanical stimuli or stress. A number of different mechanosensitive channels have been discovered, they are present in through prokaryotes and eukaryotes, their structure and sequence vary greatly and little is know about their molecular mechanism. To explore the gating mechanism of mechanosensitive channels we mainly focused on the mechanosensitive channels of large conductance (MscL), as MscL is the most studied mechanosensitive channel and often used as a model for how proteins sense membrane tension. MscL is a bacterial membrane protein that serve as last resort emergency release valve in case of severe osmotic down shock. The channel activates with applied bilayer tension, opening a large (~3 nS) mostly unselective pore.

We have explored the initial stages of MscL gating using atomistic simulations (Colombo et al, 2003). Due to the size of the system and time scales required unbiased atomistic simulations of MscL gating are currently not feasible, we therefore, developed a coarse-grained Martini model of MscL (Yefimov et al, 2008). Using Martini we can gate MscL both in planar bilayers (Yefimov et al, 2008) and vesicles (Louhivuori et al, 2010). In collaboration with a number of experimental and theoretical groups we are exploring the molecular details of MscL gating such as: the energetic effects of protein shape changes (Ollila et al 2011), structural rearrangements in presence of experimental contraints (Deplazes et al 2012), prediction of 2D-IR spectra changes upon gating (Liang et al, 2013), reversibility of gating (Ingolfsson et al, in preparation), gating kinetics and dependence on membrane properties (Ingolfsson et al, in preparation).

• G. Colombo , S.J. Marrink, A.E. Mark. Simulation of MscL gating in a bilayer under stress. Biophys J., 84:2331-2337, 2003.
• S. Yefimov, E. van der Giessen, P.R. Onck, S.J. Marrink. Mechanosensitive membrane channels in action. Biophys. J., 94:2994-3002, 2008.
• M. Louhivuori, H.J. Risselada, E. van der Giessen, S.J. Marrink. Release of content through mechano-sensitive gates in pressurized liposomes. PNAS, 107:19856-60, 2010.
• O.H.S. Ollila, M. Louhivuori, S.J. Marrink, I. Vattulainen. Protein shape change has a major effect on the gating energy of a mechanosensitive channel. Biophys. J., 100:1651-59, 2011.
• E. Deplazes, M. Louhivuori, D. Jayatilaka, S.J. Marrink, B. Corry. Structural investigation of MscL gating using experimental data and coarse grained MD simulations. PLoS Comp. Biol., 8:e1002683, 2012.
• C. Liang, M. Louhivuori, S.J. Marrink, T.L.C. Jansen, J. Knoester. Vibrational spectra of a mechanosensitive channel. J. Phys. Chem. Lett., 4:448-452, 2013.