Computer Simulation Of Membrane Cholesterol And Peptide-membrane Interaction

Biological membranes are the vital components of the biological cells. Cell plas-ma membrane isolates the cell from the surrounding environments, while the cellular endogenous membrane separate the interior of the cell into different cell organelles. The main compositions of the membrane are phospholipids, cholesterol and proteins. Biological membrane has a great function in maintaining the structure of cell, cellu-lar membrane trafficking, energy transduction and signal transmit. Therefore, under-standing the structure and properties, and the interplay between membranes and other molecules is vitally essential. In this thesis, computer simulations are applied to study the behavior of cholesterol in different membrane environments and the interaction-s between biological membranes with the membrane remodeling proteins or the cell penetrating peptide.In Chapter 1, we firstly introduce the constitute of the cell membrane and the properties of cell membrane including the mechanism, thermodynamics and dynamics aspects. We will further introduce several ongoing area of the biological membrane research. This includes the investigation of cholesterol in membrane, which is an en-riched and important metabolite in cell. It is related with many cardiovascular and cerebrovascular diseases. Besides, we will introduce the membrane remodeling be-havior in the intracellular transport process, especially, we will describe the role of the membrane remodeling protein in these processes. At last, we will introduce the interaction of the biological membrane with the external peptides. These peptides in-clude various of different categories, such as antimicrobial peptide and cell penetrating peptide.In Chapter 2,we will mainly introduce the method of molecular dynamics simu-lation, especially, we will introduce the force field parameter in molecular dynamics simulation.Besides, we will introduce the all atom and the coarse grained simula-tion method, and how the molecular simulations are used to the investigation of the biological membrane, proteins, peptide, nanoparticles and so on.In Chapter 3, with the aid of molecular dynamics simulations, we study the be-havior of cholesterol in several representative membrane environments. There is a great deal of interest and excitement in understanding the bio-behavior of cholesterol in mammalian cell membranes, which is of significant importance in exposing the patho-genesis of cardiac and brain vascular diseases. In this work, we pay attention to the relation between local lipid packing and the thermodynamic properties of cholesterols in different membranes. It is found that the entropy and enthalpy values of cholesterols in different membranes depend on the membrane lipid packing. Loose lipid packing always corresponds to favorable entropy but disadvantaged enthalpy, while dense lipid packing plays the opposite roles. We further investigate the transbilayer distribution of cholesterols in curved membrane and find that the cholesterol will adjust its distri-bution in the two leaflets of curved membrane as the two leaflets have different lipid packing style. And quantitatively, we present a simple theory model to explain the re-distribution of cholesterols in curved membrane and discuss its potential impact on the membrane deformation process.In Chapter 4, we mainly study the interactions of cell penetrating peptide with the cell membrane. Cell-penetrating peptides (CPPs) are able to transport biomate-rial such as protein and DNA across cellular membranes efficiently. In this chapter, we study the interactions between R9 peptides and asymmetric membranes by using coarse-grained molecular dynamics simulation. It is found that the peptide has the probability to penetrate through the membrane because of the electrostatic transmem-brane potential difference; however, it is difficult for a single peptide to spontaneously penetrate through the membrane while multiple peptides can translocate across mem-branes by pore-mediated process. Further, we also provide insights into the transport-ing ability of polyarginines, and find that the peptide can transport hydrophobic as well as hydrophilic particles through membranes, where the translocation of hydrophobic particle is easier than that of hydrophilic one. The present study can help better un-derstand the interactions of the peptides with cell membranes and may give some new suggestions on the design of future nanomaterials for drug delivery.In Chapter 5, we investigate the role of the N-terminal amphipathic helix of mem-brane remodeling protein in deforming the membrane. In this chapter, we combine the all-atom and coarse-grained simulations to study the interactions of the N-terminal helix of Epsin, Sarlp and Arf1 with the lipid membrane. The results of the all-atom simulations show that the inserting of the amphipathic helix will induce a decrease of the deuterium order parameter of the lipid acyl chain for the leaflet including the helix and an increase for the opposite leaflet, and the influence on the lipid packing in the present of N-terminal helix of Epsin and Sarlp is larger than that of Arfl. With the aid of coarse-grained simulations, a large system is used to observe directly the mem-brane deformation process upon multiple amphipathic helices inserting, and it is found that the N-terminal helix of Epsin and Sarlp induce a larger curvature of membrane than that of Arf1. Besides, we try to clarify how the physicochemical properties of amphipathic helix including length, net charge, hydrophobicity and hydrophobic mo-ment are associated with different membrane-bending ability of N-terminal helix of Epsin, Sarlp and Arfl. The present study can help better understand the molecular mechanism of the protein-driven membrane remodeling.In the last chapter, the thesis is summarized, and a outlook for the future works in biological membranes and membrane protein is described.