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A molecular dynamics study of NBD-cholesterol in phase separating ternary lipid mixtures

Bolt, Rosemary (2018) A molecular dynamics study of NBD-cholesterol in phase separating ternary lipid mixtures. Bachelor's Thesis, Chemistry.


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The aim of this project is to investigate the partitioning of NBD-cholesterol in phase separating bilayers with the aid of molecular dynamics simulations using the Martini 3.0 force field. Lipid domains in membranes are likely to play an important role in drug delivery and the understanding of many cell processes. However, investigating lipid domains in vivo is challenging. Fluorescent probes such as NBD-cholesterol allow imaging at very high resolution, but it cannot be assumed that these probes behave exactly the same as the untagged lipid. Therefore it is not certain that NBD-cholesterol partitions preferentially into the liquid ordered phase, as cholesterol is known to do. For simulations with experimental data, a coarse grained model of NBD with a four carbon chain, NBD-C4, was developed and compared to an atomistic mapped model. The Martini 3.0 force field is currently being modified in order to represent aromatic molecules better. The first model of NBD-C4, model A, was not very flat and the carbon chain was flipped between above and below the aromatic plane of the molecule. The design was not without flaws since the 2-1 mapping for tiny beads was not observed, and after the introduction of more constraints the model became numerically unstable. Therefore a new model, model B was created. This model kept the aromatic rings of NBD-C4 flatter, and the angle and bond distributions compared well to the mapped atomistic reference. Based on solvent accessible surface area (SASA) analysis and PMF measurements using umbrella sampling, a version of model B was chosen for use in further simulations. This model was attached to cholesterol and subsequently placed in a ternary lipid mixture, which was known to phase separate at temperatures of 320 and 330 K. Visual analysis and measuring of the contact fractions indicated that NBD-cholesterol does not behave in the same way as cholesterol. In the studied system, cholesterol partitioned into the liquid ordered phase, whilst NBD-cholesterol showed a small preference for the liquid disordered phase. More analysis regarding the orientation and exact position of NBD-cholesterol would be beneficial to understanding how and why NBD-cholesterol prefers the liquid disordered phase and for designing better probes. The results found in this study suggest that NBD-cholesterol is not a good fluorescent probe to use for studied lipid domains. However, this must be viewed with some reservation, since there are ways in which the testing system was not ideal. For example, it has been shown that NBD-cholesterol is sensitive to the polarity of the environment, so it is possible that the system that was created does not resemble an experimental system enough.

Item Type: Thesis (Bachelor's Thesis)
Supervisor name: Marrink, S.J.
Degree programme: Chemistry
Thesis type: Bachelor's Thesis
Language: English
Date Deposited: 06 Jul 2018
Last Modified: 06 Jul 2018 12:56

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