Molecular Mechanism and Dynamics of S-Deoxyephedrine Moving through Molecular Channels within D₃R

Abstract

In this article, the trajectories of S -deoxyephedrine (SBD) along molecular channels within the complex protein structure of third dopamine receptor (D 3 R) are analyzed via molecular dynamic techniques, including potential mean force calculations of umbrella samplings from the 4.5 version of the GROMACS program. Changes in free energy due to the movement of SBD within D 3 R are determined, and the molecular dynamic mechanisms of SBD transmitting along molecular channels are probed. Molecular simulated results show that the change in free energy is calculated as 171.7 kJ·mol –1 for the transmission of SBD toward the outside of the cell along the y + axis functional molecular channel and is 275.0 kJ·mol –1 for movement toward the intracellular structure along the y – axis. Within the internal structure of D 3 R, the changes in free energy are determined to be 103.6, 242.1, 459.7, and 127.8 kJ·mol –1 for transmission of SBD along the x +, x –, z +, and z – axes, respectively, toward the cell bilayer membrane, which indicates that SBD leaves much more easily along the x + axis through the gap between the TM5 (the fifth transmembrane helix) and TM6 (the sixth transmembrane helix) from the internal structure of D 3 R. The values of free-energy changes indicate that SBD molecules can clear the protective channel within D 3 R, which helps dopamine molecules to leave the D 3 R internal structure along the x + axis and to prevent them for exerting excessive neurotransmitter function. Therefore, our results suggest that SBD is effective for development as a drug for treating schizophrenia and its pharmacology is closely related to its dynamics and mechanisms within the molecular pathway of dopamine receptors.