Mechanosensitive（MS） ion channels play an important role in various physiological processes.Although the determination of the structure of mechanosensitive channel of large conductance（MscL） makes the simulation study possible,it has not so far been possible to directly simulate the gating mechanism of MscL in atomic detail.In this article,MscL has been studied via molecular dynamic（MD） simulations to gain a detailed description of the sensitivity to lateral tension and the gating pathway.MscL undergoes conformational rearrangement in sustaining lateral tension,and the open state is obtained when 2.0 MPa lateral tension is directly applied on the pure protein.During the opening process,Loop region responds to tension first,and the mechanical sensitivity is followed by S1 domain.Transmembrane（TM） bundle is the key position for channel opening,and the motion of TM1 helices finally realizes the significant expansion of the constricted gating pore.C-terminus domain presents expansion later during the TM opening.In our study,return of the whole protein to the initial closed state is achieved only in the early opening stage.During the relaxation from the open state,the TM helices are the most mobile domain,which is different from the opening process.
In micropipette aspiration experiment,increasing mechanical stress applied to cell membrane induced degranulation of mast cell as well as a current that could be inhibited by an inhibitor, which is specific for the transient receptor potential vanilloid(TRPVs) channels. To determine the sensitivity of TRPVs to membrane strain and tension, and to gain new insights into the activation mechanism of TRPVs, finite element models of mast cell and molecular dynamic simulations of human aquaporin-1are presented. During the finite element simulations, the cell membrane sustained to micropipette aspiration was simulated, and the strain distribution along membrane thickness direction was obtained. Besides, combining the finite element models of osteoblast aspirated into micropipette and other compared models, we examined the relationship between cell mechanical attributes and mechanical stimulations and presented a new perspective to determine the cell equivalent elastic modulus. Considering the indetermination of TRPV crystal structure, human aquaporin-1, one kind of the channel membrane proteins,substituting for TRPV, has been studied with molecular dynamic(MD) simulations, under different external lateral tensions which have been obtained in mast cell finite element simulations, to investigate the mechanical stimulation effects on the membrane channels. The simulations show that human aquaporin-1 undergoes significant conformational change and expands in accordance with lateral tension, which not only confirms the tendency of the previous electrophysiological experiments but also leads us to a better understanding of TRPVs. The multi-scale study combining finite element simulation and MD simulation is a significant breakthrough in the field of mechanical mechanism in cell system.
