Molecular Mechanics Of Biomembrane Fusion

Biomembrane fusion lies at the heart of many physiological processes,such as neurotransmission and targeted drug release.However,the underlying mechanism of the fusion process in molecular details has not yet been completely understood.In this dissertation,the evolution of membrane structure and the molecular regulation mechanism in the fusion process were studied by molecular dynamics simulations.The main results include the following aspects:(1)Molecular dynamics simulations was used to study the formation process of fusion pore in the initial stage of lipid membrane fusion and its molecular mechanism.The results showed that after two lipid membranes approach with each other to a critical distance,fusion pores formed on the membrane.The transmembrane voltage generated by the close contact of membranes is the driving force for the rapid pore formation.In addition,the membrane tension generated by the fusion proteins plays an important role in the stability and duration of the fusion pores,which in turn may regulate the fusion pathways' chosen between the modes of Kiss-and-Run and Full-Fusion.(2)The mechanism of lipid membrane pore formation under electric field was studied by molecular dynamics simulations.The results showed that the electric field reduces the energy barrier of water molecules penetrating into lipid membrane,and water molecules would prefer to penetrate into a membrane from one side with lower energy barrier.When the transmembrane voltage is gradually increased to a critical value,several water molecules driven by the electric field penetrated into membrane to form an water chain.The lipid head groups moved into the membrane following the water molecules and a transmembrane hydrophilic pore formed.(3)The impact of different lipid compositions on the evolution of hemifusion structure in the fusion process was studied by molecular dynamics simulations.The results showed that the hemifusion structure could be an unstable state for both phosphatidylcholine(PC)and phosphatidylserine(PS),the fusion process will suffer a transient intermediate state and to reach full-fusion shortly.Phosphatidylethanolamine(PE)and cholesterol will delay the formation of full-fusion pores.In addition,membrane pore formation near the hemifusion region will lead to contents leakage during fusion process,and cholesterol can significantly suppresses the probability of contents leakage by decreasing the penetration of water molecules into the lipid membrane.(4)The curvature correlation of interaction between complexin and lipid membrane has been studied.The simulation results showed that the interaction bwtween complexin and lipid membrane was due to the insertion of complexin's C-terminal hydrophobic side chains into the membrane's hydrophobic region.The number of membrane's hydrophobic regions exposed to the solution,i.e.,the number of membrane defects,is positively correlated with the curvature of membrane.Therefore,goes along with the increaseing of membrane curvature,the number of membrane defects increased,which will resulting in that complexin's C-terminal hydrophobic side chains are more likely to interact with curved membrane,so that the interaction between complexin and lipid membrane became curvature correlated.(5)Through molecular dynamics simulations,it was found that the N-terminal acetylation of ?-synuclein preserve from oligomerization significantly.The results indicated that N-terminal acetylation disrupt the hydrogen bond network in the ?-synuclein oligomers,destabilize the oligomerization state and preserve the formation of ?-synuclein from oligomers.