Coarse-Grained Simulations Of The Biomembrane-Protein Interaction And The Transmembrane Transport Of Nanoparticles

As an important building block of cells, biomembrane participate inmany activities of the cells, like endocytosis, exocytosis, cell division, cellmigration, and cell signal transduction. Thus, investigating the structure andproperties of biomembranes is of quite importance to understand deeply itsfunctions in various cell activities. It is noteworthy that besides the lipidmolecules, there exist different membrane proteins (e.g., transmembraneprotein, anchored protein, and peripheral protein) in membranes, which playimportant roles in their biological function. However, because the membraneis of a dynamic structure with high complexicity, its structure and function indifferent cell activities are still not well understood. On the other hand, as thedevelopment of computer technology, it becomes possible for the use ofmolecular simulation to investigate a larger biological system in a longer timescale. Therefore, in this work we mainly use the molecular simulation toinvestigate the interaction between biomembrane and protein and thetransmembrane transport of nanoparticles (NPs).1. First, in this work we investigated the molecular mechanism ofmembrane-membrane protein interactions. The research contents and findingsare summarized as follows.(1) Using N-varied Dissipative Particle Dynamics (DPD) simulationmethod, we investigated the relationship between clustering of anchoredproteins and the membrane deformation. Our simulation results reveal that theaggregation of anchored proteins is mainly dependent on the hydrophobiclength. Besides, we found that the membrane curvature is not only dependenton the membrane surface tension, but also strongly affected by the extent ofclustering of anchored proteins. In general, the protein aggregation has aintrinsic curvature which bends the membrane in a way like scaffoldingmechanism. Therefore, this work may provide a new mechanism for the membrane deformation. On the other hand, our simulation results indicate thatthe protein aggregation and distribution can sense the local membranecurvature, which can help us to understand the distribution of proteins indifferent membrane environment.(2) According to the fact that the membrane proteins can sense the localmembrane curvature, we further investigated the effect of local membranecurvature on the interaction between neighboring membrane proteins. Here weused vesicles with different sizes to model the effect of local membranecurvature on the protein interaction. Our simulation results reveal that theinteraction between two transmembrane proteins is not only dependent on thehydrophobic mismatch, but also strongly affected by the local membranecurvature. On the other hand, we found that proteins with differenthydrophobic length can disturb the local membrane curvature, and furtheraffect the whole morphology of the vesicle.(3) Besides the role of membrane proteins in membrane deformation,we also investigated the coupling of the clustering of anchored proteins indifferent leaflets of a cellular membrane. Our simulation results reveal that thesignal transduction can be mediated by coupling of clustering of anchoredproteins in different leaflet, without the existence of transmembrane proteins.Three different coupling patterns, including face-to-face clustering,interdigitated clustering, and weak coupled clustering are observed in oursimulation. Besides, we found that the extent of protein aggregation can alsobe affected by different coupling patterns. Therefore, we have proposed a newmechanism for signal transduction: the coupling of clustering of anchoredproteins in both leaflets.(4) Due to the importance of bundling of biopolymers in differentcellular activities, we investigated the helical bundling of anchoredbiopolymers by using Brownian Dynamics simulation technique. Oursimulation results reveal that the helical bundling of biopolymers is the resultof competition between inter-polymer attraction and inner bending stiffness.Different assembly patterns, including helical bundle, parallel bundle,disordered hemisphere cluster, and unbundled monomers were found,depending on the intrinsic properties of the biopolymers (e.g., polymer length,intrinsic stiffness, and inter-polymer adhesion strength). In addition, oursimulation demonstrated that the bundle formation reinforces the bending stiffness, and the stiffness is further enhanced by helical bundling. For thedynamic aspect, both hierarchical bundling and nonhierarchical bundling wereobserved.(5) Membrane channel is one kind of strongly confined space, and smallbiomolecules are thought to present different structures and properties instrongly confined space. Therefore, we investigated the tight packing of linearmolecules in confined space by performing molecular dynamics simulations.Our simulation results reveal that both single site and two site molecules canform a series of chiral and achiral structures in cylindrical pores with differentsizes, while longer four site molecules can form ordered helical structures incylindrical pores with only certain diameters. Besides, linear molecules withdifferent length can response differently as the temperature increases.Therefore, this work can help us to understand the structure evolution of smallbiomolecules when they are confined in the membrane channels.2. As the second part of the dissertation, we also investigated thetransport of nanoparticles across the biomembrane. The research content andfinding are summarized as follows.(1) Using N-varied DPD simulation method, we investigated theinteraction between one single nanoparticle and the lipid membrane. Oursimulation results reveal that depending on the membrane surface tension,ligan density and nanoparticle size, four kinds of membrane responses areobserved: receptor-mediated endocytosis, NP adhesion, NP penetration, andmembrane rupture. Both receptor mediated endocytosis and NP adhesionindicate that the ligand coated NPs can be used as drug delivery materials,while NP penetration and membrane rupture demonstrate that the NPs caninduce cytotoxicity in some extent. Therefore, the conclusions of this workcan provide quantitative guidelines for design of drug delivery materials withlower cytotoxicity and higher drug delivery efficiency.(2) In the receptor-mediated endocytosis of NPs, we further investigatedthe internalization pathway of multiple, small NPs. Our simulations reveal thatthe internalization of multiple NPs is in fact a cooperative process. Besides,different internalization pathways were found to depend on NPs size, NPsconcentration, and size difference between neighboring NPs.(3) After the investigation of interaction between rigid NPs andbiomembrane, we then concentrated on the interaction between a soft elastic vesicle and lipid membrane. Our simulation results reveal that the vesicle caninteract with a lipid membrane via as many as five different ways: vesiclefusion, vesicle hemi-fusion, vesicle adhesion, vesicle rupture, and vesicleendocytosis. In addition, different interaction properties are found to dependmainly on adhesion strength of vesicle, membrane surface tension, and vesicletension.