Poration of Biological Membranes by Antimicrobial Peptides and Pressure, Insights from Computer Simulations

The plasma membrane is the boundary of the cell that separates the outside world from its interior. It is the first barrier that any exogenous compound faces upon transferring to the cytoplasm. Additionally, this boundary plays a variety of biochemical roles for the cell including energy transfer, signal transduction, solute transport, etc. Lipids, proteins, and carbohydrates are three major components of the plasma membrane and their type and percentage differs depending on the specific cell, organelle, or tissue type. The fact that the plasma membrane keeps the integrity of the cell intact can play different potential therapeutical roles depending on the context; opening or disturbing the barrier versus healing or repairing it. More specifically, when the cell membrane we approach belongs to an opportunistic organism such as a bacterium or a virus, we tend to disturb the integrity of their membrane to damage the invading organism (antibiotic therapy). On the other hand, in the context of exposure of the neuron cells to uncontrolled shock waves (blast waves) we tend to avoid damage to the cell membrane since the outcome correlates with brain damage and psychological complications. Understanding the underlying mechanisms for restoring the integrity of a damaged plasma membrane using certain compounds (e.g. polymers) provides invaluable information in our therapeutical approaches. There are a variety of experimental methods available for membrane research such as X-ray and neutron scattering, AFM, Fluorescence probing, and NMR. Additionally, molecular dynamics computer simulations can also be used in different research settings, to provide more atomistic insight into the processes that take place in the plasma membrane. A variety of force fields are available which provide different levels of atomic representation of the system in question and open the door for more detailed understanding of the nature of the cell membrane and how it behaves. In this thesis, we used molecular dynamics computer simulations to ask two major questions. First, what mechanisms are involved in opening of the plasma membrane? We studied Antimicrobial peptides (AMPs) and how their mechanism of action can be envisioned by computer simulations. We also investigated shock wave induced nano-bubble collapse and its impact on the plasma membrane. Second, what mechanisms membrane sealants employ to restore the integrity of a damaged membrane? More specifically, we provided molecular pictures of the process of membrane sealing by triblock co-polymers, or Poloxamers.Doctor of Philosoph