Molecular dynamics simulation of d-Benzedrine transmitting through molecular channels within D₃R

Abstract

Dex-Benzedrine (known as d-Benzedrine or SAT) acts in dopamine receptors of central nerve cell system. In clinic, SAT is used to treat a variety of diseases; meanwhile, it has dependence and addiction. In order to investigate the pharmacology and addiction mechanisms of SAT as a medicine, in this paper, we have studied the structure of DR complex protein with SAT, and based on which, using potential mean force with umbrella samplings and the simulated phospholipid bilayer membrane (or POPC bilayer membrane), the molecular dynamics simulation was performed to obtain free energy changes upon the trajectories for SAT moving along the molecular channels within DR. The free energy change for SAT transmitting toward the outside of cell along the functional molecular channel within DR is 83.5 kJ mol. The change of free energy for SAT to permeate into the POPC bilayer membrane along the protective molecular channel within DR is 87.7 kJ mol. Our previous work gave that the free energy for Levo-Benzedrine (RAT) transmitting toward the outside of cell along the functional molecular channel within DR is 91.4 kJ mol, while it is 117.7 kJ mol for RAT to permeate into the POPC bilayer membrane along the protective molecular channel within DR. The values of free energy suggest that SAT relatively prefers likely to pass through the functional molecular channel within DR for increasing the release of dopamine molecules resulting in a variety of functional effects for SAT. The obtained results show that the pharmacology and addiction mechanisms of SAT as a drug are closely related to the molecular dynamics and mechanism for SAT transmitting along molecular channels within DR.

Disordered linkers in multidomain allosteric proteins: Entropic effect to favor the open state or enhanced local concentration to favor the closed state?

“…Coarse-grained models have been widely used in protein studies, [31][32][33][34][35] especially for large conformation movements. [36][37][38] We adopt a coarse-grained native-centric G o-like model, [39][40][41][42] to calculate the free energy profile of a protein with two domains connected with a disordered linker.…”

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

“…On the contrary, our research results repeatedly show no occurrence of a zigzag type PMF potential energy surface, which means good overlap of the histogram figures. 22,24,25 This good overlap of the umbrella samples suggests that the WHAM method can be effectively used to calculate the reliability of Δ G values. 43 In addition, although there is no direct comparison of the experimental data, the reliability of free energy obtained by molecular dynamics simulations can be proved by comparing relevant experiments.…”

“…Our results show SBD to have a very unique character preferably moving through a protective channel unlike some molecules preferably moving through the functional channel. 24,25 SBD moves along the functional molecular channel within D 3 R toward the outside of the cell, with a free-energy change of 171.7 kJ·mol –1 , whereas movement toward intracellular orientation induces a free-energy change of 275 kJ·mol –1 . Furthermore, SBD trajectories along the protective molecular channels within D 3 R in the x +, x –, z +, and z – axes toward spaces in the cellular membrane result in free-energy changes of 103.6, 242.1, 459.7, and 127.8 kJ·mol –1 respectively.…”

Structural Basis and Mechanism for Vindoline Dimers Interacting with α,β-Tubulin

“…The pressure coupling adopted Parrinello–Rahman with the coupling time constant of 2 ps. Then, the system temperature was set to 310 K, and the pressure was set to 1.0 atm . We used VMD and Chimera programs to do the visual analysis for the output trajectory data.…”

“…Then, the system temperature was set to 310 K, and the pressure was set to 1.0 atm. 63 We used VMD 64 and Chimera 65 programs to do the visual analysis for the output trajectory data.…”