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
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.