Dynamics and Electrostatics of Membrane Proteins using Polarizable Molecular Dynamics Simulations

Membrane proteins are critical to many biological processes, including molecular transport, signal transduction, and cellular interactions. Through the use of molecular dynamics (MD) simulations, we are able to model this environment at an atomistic scale. However, traditionally used nonpolarizable force fields (FF) are thought to model the unique dielectric gradient posed by the lipid environment with a limited accuracy due to the mean field approximation of charge. Advancements in polarizable FFs and computing efficiency has enabled the explicit modeling of polarization responses and charge distribution, enabling a deeper understanding of the electrostatics driving these processes. Through the use of the Drude FF, we study three specific model systems to understand where explicit polarization is important in describing membranes and membrane proteins. These studies sought to answer the questions: (1) How does explicit electronic polarization impact small molecule permeation and localization preference?, (2) What electrostatic interactions underlie membrane protein secondary structure?, and (3) How do conformational changes propagate between microswitches in G-Protein Coupled Receptors? In this work, we show small molecule dipole moments changing as a function of localization in the bilayer. Additionally, we show differences in the free energy surfaces of permeation for aromatic, polar, and negatively charged species reliant upon force field used. For secondary structure, we showed key interactions which aided to stabilize model helices in bilayers. Finally, we showed potential inductive effects of key microswitch residues underlying prototypical G-Protein coupled receptor activation. This dissertation has helped to show the importance of including explicit polarization in membrane protein systems, especially when considering interactions at the interface and modeling species with charge. This work enables a refined view of the electrostatics occurring in membranes and membrane protein systems, and in the future, can be used as a basis for methodologies in computer aided drug design efforts.