Theoretical and computational modeling of the interactions of peptides and proteins with lipid bilayer surfaces
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This dissertation combines computational and theoretical modeling with experimental data to advance our understanding of peptide-lipid interactions, leveraging coarse-grained (CG) molecular dynamics (MD) simulations and atomic force microscopy (AFM)-based force spectroscopy to elucidate these essential biological processes. We investigated the impact of polypeptide length on membrane interactions using a series of short, homologous peptides, revealing a linear dependence of free energy barriers and intrinsic dissociation rates on peptide length. Another study examined the effect of primary structure by varying guest residue species and positions within host-guest pentapeptides, finding significant effects of terminal residues on interactions with zwitterionic and anionic lipid bilayers and identifying multiple dissociation pathways. Additionally, we applied and compared several computational techniques for analyzing AFM force spectroscopy data, proposing machine learning methods for improved analysis. These findings suggest that peptide-membrane interactions might be more complex than previously understood, often requiring multiple dissociation pathways. Finally, we extended CG MD simulations to study a large peripheral membrane protein, providing insights into interactions at the lipid membrane surface from its dominant binding regions. This study highlights limitations in current methods and suggests alternative approaches for studying complete proteins.
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Ph. D.