Molecular dynamics modelling of biomolecular interactions with lipid membranes and novel coarse grain lipid model development : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Albany, New Zealand

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Massey University
Lipids comprise a key component of the cellular membrane and are essential to many biological processes. In silico investigations provide valuable opportunities to study the dynamics and structure of biological molecules, such as lipid membranes and the molecules that interact with them, at near atomic resolutions. In the context of this thesis three research projects were undertaken with a focus on lipid membrane simulations. The structure and dynamics of the novel antibacterial battacin analogue peptides and their interactions with model membranes of the common pathogenic gram positive and gram negative bacterial species Staphylococcus aureus and Escherichia coli were studied. Antibacterial peptides are a key area of research due to their potential medicinal applications in overcoming the current antibiotic resistance crisis. However, detailed knowledge of their mode of action is often lacking. The peptides were to found to insert into the bacterial membranes, facilitated by the insertion of the fatty acid moiety, and showed strong affinity for all three types of membranes studied. Antifreeze protein 1 (AFP1) is critical to cell survival at near freezing temperatures. Structural analysis of the behavior of AFP1 is presented, including a study of its possible aggregation. Interactions of AFP1 were studied in conjunction with a model of a typical cell membrane. AFP1 units were found to be flexible in solution, adopting a variety of non α-helical structures. In certain cases, two AFP1 proteins aggregated together and interacted with each other. Furthermore, AFP1 interacted with the unsaturated lipid membrane, coming to rest on its surface, providing insight into the freezing damage prevention mechanism. Finally, in order to facilitate simulation of larger biological membrane systems, a novel supra-atomic phospholipid model was proposed, and model parameters developed for the common lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). The model is based on and ultimately compatible with the GROMOS 54a8 atomic-level force field103 including the GROMOS coarse-grained water model111. It is also polarisable, unlike many popular supra-atomic models. The DPPC model was developed following a bottom-up approach, and is intended to pave a way for stepwise parameterisation of other lipids, to build a library of “plug and play” lipid parameters.
Lipid membranes, Antibacterial agents, Antifreeze proteins, Phospholipids, Molecular dynamics, Computer simulation, Research Subject Categories::TECHNOLOGY::Bioengineering