Extending the Amber Lipid Framework for Atomistic Modeling of Organic-Lipid Conjugates

Abstract

We present a method for extending the Amber Lipid Framework, currently Lipid14/Lipid17, in order to model lipid-conjugated organic molecules using all-atom molecular dynamics simulations. The approach retains the “plug-and-play” modularity of the Amber Lipid Framework, using a fixed-charge capping strategy along with the RESP protocol to fit charges for molecular dynamics simulations. It allows the use of atom types derived from the lipid force field or from other compatible parameter sets, such as the General Amber Force Field. Here, we highlight application of the strategy to modeling an electron paramagnetic resonance (EPR) spin-label probe as well as lipid-linked prodrug compounds. We validate the behavior of the simulation models through comparison with experimental data. The simulations enable physical characterization as well as visualization of the lipid conjugates and their manner of incorporation in lipid bilayers. Moreover, the simulations are found to be insightful for interpreting experimental data and valuable as a tool for smart design of additional lipid-conjugate compounds. The method of extending the Amber Lipid Framework is straightforward, although nontrivial to implement.