Modelling short peptides in solution and at the interface
The way in which neighbouring particles interact with each other is fundamental to all chemical phenomena, where the specific blend of intermolecular forces and geometric conformation dictate the properties of any system. This thesis discusses the importance of intermolecular interactions to phenomena witnessed for simple systems that may hark back to the origins of life, as well as complex systems where macromolecules display high affinity for solid surfaces.In the first chapter, we explore the relationship between peptide sequence andstructure. Using the example of catalytic peptides that are able to perform amide bond condensation, we examine the possibility of short peptide sequences adopting a conformation that supports an active site analogous to that found in protease enzymes such as subtilisin using molecular dynamics (MD). In this study we define a catalytic triad by convergence of an acid, histidine and hydroxyl residue below 4 Aͦ. It was found that each of the three sequences studied could form a triad structure; however due to the flexible nature of the peptides this conformation was short-lived. We concluded that the catalytic activity of these peptides originated from their ability to form protease active site analogues and that experimentally observed Kcat rates, lower than that observed for enzymes, was a result of the flexible nature of the peptides.In Chapter two, we examine the properties of single amino acids with solid surfaces. We use Au 111 as our model since there are numerous cases of peptides with a high affinity for gold. The aim of this study was to calculate the relative binding free energies of nine amino acids that make up the gold binding peptide GBP1. Using Steered Molecular Dynamics (SMD) simulations we follow the change in free energy of each individual amino acid as it is pulled from the bound state to the bulk. We find that aromatic amino acids and those containing heteroatom side chains show greater affinity for the metal surface, by around 14 -17 kcal mol-1, compared to aliphatic amino acids. These findings provide a basis for creating and understanding the interactions between peptides and solid surfaces.Following the study of individual amino acids with gold, we perform a comprehensive free energy study on a gold binding peptide, identified from combinatorial library experiments, in order to fully understand the influence of both electronic and conformational characteristics of peptides on the strength of interaction with the surface. By once again utilising SMD, we find that the interaction of the amino acid side chains with both the surface and the solvent dictate the affinity of GBPs for gold. The ability for a peptide to form strongly stabilising interactions with water will weaken its ability to bind to the surface as the adsorbed state becomes less favourable relative to the solution state. These findings demonstrate that design of peptides for binding to surfaces relies on a delicate balance between affinity for the solid and for the solution. Furthermore, we conclude that simple combination of single amino acid binding free energies do not provide sufficient insight into the affinity of the peptide for gold.The fourth chapter focuses on conformational behaviour of GBPs under saturated conditions. Through increasing peptide concentration fourteen times, the way in which peptides interact with both the surface and each other is investigated in order to obtain a realistic, high quality model of the system.
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