Membranes and macromolecules: uncovering complexity in simulation

Abstract

In molecular dynamics (MD) simulations, we use simplified physical laws to define a representative universe so that we may gain insight into phenomena that occurs in our own. MD simulations have become indispensable tools in biomolecular and pharmaceutical research, allowing exploration of complex biological systems at a spatiotemporal resolution and breadth still unparalleled by experimental techniques. However, the usefulness of MD simulations is limited by the extent to which behaviour observed in simplified simulations is representative of physical reality.

The following thesis explores the impact on simulations of biomolecular systems such as membrane proteins of both the various parameter sets used to define the physics of MD, as well as the degree to which the composition of the system reflects the complexity of reality. The first chapter begins by comparing the performance of common protein force fields on the dynamics of a large membrane transporter protein, P-glycoprotein. The second chapter further investigates the impact of different popular methods for assigning electrostatic parameters on small molecule hydration free energies and the implications for macromolecules such as polymers. Finally, the third chapter examines the dynamics of membranes. Long regarded as the simple background milieu of membrane proteins, the work in this thesis highlights the importance of membrane composition and complexity on the dynamics and biophysical properties of the proteins that sit within them. Overall, this thesis probes and quantifies various aspects and decisions in studying biomolecular systems through molecular dynamics simulations. Show more