Molecular Dynamics Studies of Interfacial Effects on Protein Conformation

A better understanding of life at a microscopic level permits the formulation of better drugs, the imitation of biological processes for technological applications, and the prediction of the impact of pathogenic substances. At the heart of biological molecular processes lies the interaction of polypeptides with solvent and lipid environments; technological applications rely on the interaction of polypeptides with inorganic substrates. Molecular dynamics (MD) simulations provide a means by which these interactions may be examined in atomic-level detail, offering increasing speed and accuracy, as well as applicability to progressively larger system sizes and longer simulation times. This thesis describes the application of molecular dynamics simulation technique to several systems in which interfacial effects on protein conformation are of interest. In the first chapter, a detailed description of MD simulations is presented. The physical basis for the methodology is discussed, followed by a description of the algorithms implemented to carry out the simulations. The chapter concludes with a description of the techniques used to initialize, carry out, and analyze simulations. The second chapter describes the application of MD simulation to a system of biological interest [6]. It is well-known that a lipid bilayer membrane provides an impermeable barrier around living cells, and that transmembrane proteins, often comprising several non-bonded subunits, form pores and channels in the membrane to permit the passage of resources and waste as well as regulate osmotic pressure. It is still unclear, however, how these proteins are incorporated into the membrane and how complex transmembrane structures are formed. A model system, consisting of a transmembrane helix dimer in a spherical aggregate of lipids (micelle) is examined and compared to a mutant system by way of MD simulation; the spontaneous aggregation of lipids into a micelle surrounding the protein from an initially random configuration is also described, and compared to a theoretical diffusion model. The third chapter describes the application of MD simulations to a system of technological interest: a gold-binding protein in contact with a gold crystal surface [7]. The biological control of inorganic crystal formation, morphology and assembly is of interest to biologists and biotechnologists studying hard tissue growth and regeneration, as well as to material scientists using biomimetic approaches for control of inorganic material fabrication and assembly. Structure predictions for gold binding protein sequences, originally selected by combinatorial techniques, are presented. Molecular dynamics simulations were carried out using solvated polypeptides at the gold surface, and the dynamics of the binding process and the effects of surface topography on binding affinity are described. Lastly, in an appendix, a method for determining the potential of mean force from a steered molecular dynamics simulation is presented [8].U of I Onlydissertation/thesi