Molecular Dynamics Study On Conformational Changes Of Translocon Channel In Protein Translocation

Proteins transport must be accomplished by the Sec protein-conducting.The process in which Sec-assisted the membrane integration or proteins translocation is ubiquitous and essential in all biological cells.The Sec61 translocon is in eukaryotes,which is a complex consisted of three subunits(Sec61?,? and ?).The Sec61? subunit is a channel structure composed of 10 transmembrane(TM)helices,in which TM2 and TM7 helices as a lateral gate.In the Sec61? channel,if the nascent peptides are integral membrane proteins,the lateral gate opens,allowing they to be inserted into the membrane through the lateral gate,otherwise the lateral gate is not opened and the nascent peptides are secreted out of the membrane.During the insertion process,changes in the structure of the Sec61? channel are critical for membrane insertion and maintenance of the membrane barrier.In recent years,although some progress have been made in the study of the structure of Sec61? channel,the mechanism of structural resilience,lateral gate,pore ring and plug during the conformational transformation of channel remains unclear.Elucidating the molecular mechanism of Sec61? channel-assisted membrane integration has been a hotspot in the field of biochemistry.Due to experimental limitations,computer simulation has become a powerful tool in this field.In addition,the Sec61? channel-assisted protein membrane insertion process requires the cooperation of many related molecules.The membrane insertion process is extremely complicated,and its space-time scale is large.The traditional all-atom simulation cannot achieve the space-time scale required by this process.Therefore,this paper constructed the MARTINI coarse grained model of Sec61?/membrane/water,and performed microsecond scale molecular dynamics simulation on the structural changes of Sec61?,studies the structural resilience of Sec61 channel,as well as the linkage mechanism of lateralgate,pore ring and plug.The results showed that after the nascent peptides insert into the lipid phase,the lateral gate could quickly return to the partially closed state(at this time,the pore diameter was about 7 (?)),triggering the corresponding position change of the pore ring residues to form a perfect ring structure,while the plug keeps the channel blocked.This series of positional changes revealed the strong structural resilience of Sec61? channel,which verified the prediction of experimental results.We find that the Sec61? channel formed a more commodious entrance at external side than cytoplasm side,which is theoretically more conducive to the penetration of water molecules,but no penetration of water molecules through the channel is observed in the simulation.In the two-microsecond coarse-grained simulation,the partially closed state of the lateral gate of Sec61? channel remains stable,and the angle change between TM2 and TM7 helices is independent of the degree of opening of the lateral gate.After applying harmonic suppression to the TM2 and TM7 helices to keep the lateral gate open,the pore ring structure cannot be restored to a perfect ring,but residue I292 of the ring is still at the center of the channel,and the residue L449 is moved upward by about 5 (?),in the same plane as the residues I183 and I292,while the plug moves about 2 (?) toward the ring.The change of the plug position compensates for the defect that the pore ring residue cannot be looped,and maintains the permeability barrier function of the Sec61? channel when the lateral gate opened.The permeation of water molecules was also observed in the simulation.Since the plug moves toward the ring and blocks the channel together with the ring,the water molecules penetrate to the other side of the membrane along the TM2 helices through the open lateral gate.The molecular mechanism of water permeation process proposed in this simulation study,which filled in the blank of experimental research.