Accelerated Molecular Dynamics Simulations of Drug Binding to a Muscarinic G-protein Coupled Receptor and Hybrid Finite Element-Brownian Dynamics for Diffusion of Charged Particles

Yinglong Miao
Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093


Two studies on the diffusion of charged drug molecules or model particles are discussed in this talk. First, accelerated molecular dynamics (aMD) is proposed to simulate drug binding processes to a muscarinic G-protein coupled receptors (GPCR), particularly the M3 receptor, which has targeted for treating many human diseases, including cancer, diabetes and obesity. Specifically, aMD simulations are performed on the binding of three chemically diverse drug molecules but all with one positive charge, i.e., the antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecondtimescale conventional MD (cMD) simulations, aMD greatly accelerates the binding of TTP to the extracellular allosteric site and ACh to the orthosteric site of the M3 receptor. Furthermore, aMD also captured binding of ARc to the receptor orthosteric site in 200 ns simulation time. This demonstrates the applicability of aMD to protein-ligand binding, in addition to the enhanced sampling of protein conformations. Second, I will discuss the development of a hybrid finite element-Brownian dynamics (FE-BD) approach for modeling the diffusion of charged particles. Hybrid FE-BD was proposed in a previous study, but it focused on only neutral particles without physical interactions. Here, it is extended to charged particles that possess electrostatic interactions. Preliminary results are obtained on 1D diffusion model system. Problems and further extension to the 3D diffusion system will be discussed.