Molecular dynamics studies of membrane models and membrane active peptides

Abstract

Starting from a simple membrane model, we focus on a methodological issue of truncating Van der Waals (VDW) interactions when simulating lipid bilayers. This issue is frequently ignored in literature and various VDW cutoff lengths have been reported in use. In this work, we show that truncating VDW interactions at different length has significant effects on lipid properties and more importantly we determine the appropriate cutoff by following the original force field development philosophy. The new determined cutoff shows improved agreements with experimental results. We emphasize the importance of correct and consistent treatment of VDW interactions in simulating lipid bilayers.

We extend our membrane model to study its interaction with a cell penetrating peptide (cR9). Cell penetrating peptides are short peptides that can translocate across membranes in an energy-independent manner. They are a promising agent to deliver drugs into cells but the mechanism of how they translocate through membrane is still unclear. A water pore assisted translocation model was proposed by Herce and Garcia in 2007, and this work focuses on understanding this model from a thermodynamic perspective. However, calculating a converged free energy profile for this system is challenging, due to various slow relaxation degrees of freedom in the system. To tackle this problem, we propose an idea to calculate the free energy along two different paths: one involves a water pore formation and the other does not. We find that cR9 translocating across a membrane along a water pore path requires much less energy than along a water pore free path. This work provides thermodynamic evidence to the previous pore-assisted translocation model.

Finally, we study a more realistic membrane model by adding a second lipid type. It is often difficult for simulations of such a system to reach lateral equilibrium due to the slow lipid diffusion. To solve this problem, we apply a method named "replica exchange with solute tempering" (REST) to accelerate lipid diffusion. Compared to traditional molecular dynamics, REST increases the lipid lateral diffusion by an order of magnitude. More importantly, REST is efficient in computational resources due to the fact that it only accelerates the sampling of the relevant part of the system. By using this method, we obtain a high resolution of radial distribution functions between different molecular types.

In this thesis work, we focus on using molecular dynamics simulations to study lipid bilayers and their interactions with membrane active peptides.