Computer simulation of lipids and DNA using a coarse grain methodology

The nucleus of the eukaryotic cell contains a large pool of lipids together with structural<br/>proteins and genomic DNA. The project aim was to develop simple and robust lipid and<br/>DNA models that will allow for these complex molecules to be mixed together in order to<br/>elucidate the possible interactions. The large percentage of lipids found within the nucleus<br/>makes it likely that they exist in aggregates, although the actual role and structure in which<br/>they exist is unknown.<br/><br/>While there has not been substantial work done to model such interactions between lipids<br/>and DNA in order to better understand the interactions within the nucleus, a substantial<br/>body of work exists on lipid/DNA complexes in relation to gene therapy. These simulations<br/>in many cases however, are too simple and the structures formed are pre-imposed to a certain<br/>degree. Our model would attempt to simulate these interactions without such pre-imposed<br/>conditions relying solely on interactions between the particles to drive the structures being<br/>formed. A coarse graining approach in which several groups of atoms are subsumed into<br/>single interaction sites was deemed suitable given the complexity of modelling a mixture of<br/>DNA and lipids, together with the solvent and ion environment. In this regard new models<br/>of lipids, DNA, ion and solvent models were developed in a purpose built molecular dynamics<br/>package called LANKA-Lipid And Nucleic acid Komputer Algorithm.<br/><br/>The lipids in the model are represented as polar ellipsoids and the solvent as spheres with<br/>dipoles embedded within them. The interactions between the lipids and solvent are modelled<br/>using the Gay Berne potential. The developed lipid model was able to self assemble into a<br/>stable bilayer phase and reproduce many bilayer properties of a liquid crystal phase. The<br/>model was then extended to capture some of the other lipid phases seen in nature, including<br/>lyotropic phase transitions.<br/><br/>A simple study of lipid mixtures has also been undertaken during this period. The<br/>importance of considering multicomponent lipid systems has increasingly been highlighted in<br/>the literature to make the lipid models more realistic. The developed lipid models are simple<br/>enough to extend and attempt to simulate the formation of lipid rafts and domain formation.<br/>Simulation of DNA in the past has largely focused on atomistic studies. While these have<br/>proved valuable they do not consider the macroscopic length scales of the molecule. Simplified<br/>models trying to capture long length scales have had to compromise on the molecular level<br/>detail. Coarse grain models while trying to bridge the gap have also remained largely idealistic<br/>in nature.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2009

Author dc:creator

• Chellapa, George

Advisor dc:contributor.advisor

• Essex, Jonathan W.