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. 2007 Sep 1;93(5):1431-41.
doi: 10.1529/biophysj.106.088500. Epub 2007 Apr 27.

Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations

Wei Fu  1 , Jianhua Shen, Xiaomin Luo, Weiliang Zhu, Jiagao Cheng, Kunqian Yu, James M Briggs, Guozhang Jin, Kaixian Chen, Hualiang Jiang
Affiliations

Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations

Wei Fu et al. Biophys J. .

Abstract

(-)-Stepholidine (SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have dual function as a dopamine receptor D1 agonist and D2 antagonist. Insights into dynamical behaviors of D1 and D2 receptors and their interaction modes with SPD are crucial in understanding the structural and functional characteristics of dopamine receptors. In this study a computational approach, integrating protein structure prediction, automated molecular docking, and molecular dynamics simulations were employed to investigate the dual action mechanism of SPD on the D1 and D2 receptors, with the eventual aim to develop new drugs for treating diseases affecting the central nervous system such as schizophrenia. The dynamics simulations revealed the surface features of the electrostatic potentials and the conformational "open-closed" process of the binding entrances of two dopamine receptors. Potential binding conformations of D1 and D2 receptors were obtained, and the D1-SPD and D2-SPD complexes were generated, which are in good agreement with most of experimental data. The D1-SPD structure shows that the K-167_EL-2-E-302_EL-3 (EL-2: extracellular loop 2; EL-3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain and the binding of SPD. Based on our modeling and simulations, we proposed a mechanism of the dual action of SPD and a subsequent signal transduction model. Further mutagenesis and biophysical experiments are needed to test and improve our proposed dual action mechanism of SPD and signal transduction model.

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Figures

FIGURE 1
FIGURE 1
Overview of the SPD-D1/POPC/water system. D1 is shown in ribbon; the hydrophobic chains of bilayer lipids are labeled H; and the lipid carbonyl oxygen atoms, choline N atoms, and P atoms are represented in a space fill model (labeled P), and water as W; the 3-D size of the whole system was also labeled. The SPD in binding site was amplified and shown in a stick model.
FIGURE 2
FIGURE 2
Energy changes along MD simulations. (A) D1 simulation system. (B) D2 simulation system. Ten conformations shown in dotted line were identified with two criteria: lower potential energy and obvious geometrical difference among different conformations. Among them, the conformations at 2630 ps in the MD trajectory of the unliganded D1 and that at 3310 ps in the MD trajectory of unliganded D2 have the lowest binding energies toward SPD and were selected as the conformations most probably active.
FIGURE 3
FIGURE 3
Representative conformations of the D1 (A) and D2 (B) receptors during the open-closed process of the binding site as observed from MD simulations. A dashed arrow line indicates the position of the “mouth”, and a double arrow dashed line shows the “mouth” opening. All of the conformations are shown in the style of molecular surface colored by electrostatic potential. The red color stands for negative electrostatic potential, and the blue for positive potential.
FIGURE 4
FIGURE 4
Distance fluctuations during the MD simulations. (A) Distance from Nζ of K-167 (EL-2) to Cδ of E-302 (EL-3) of the D1 receptor; (B) distance from Cγ of D-178 (EL-2) to the centroid of the aromatic side chain of Y-408 (EL-3) of the D2 receptor. The open and closed conformations in Fig. 3 are shown in the dotted lines in Fig. 2.
FIGURE 5
FIGURE 5
Hydrogen-bonding network among K-167, D-173, E-302, and bridging water molecules in D1.
FIGURE 6
FIGURE 6
Binding modes of SPD in the D1 (A, C, and E) and D2 (B, D, and F) receptors. (A and B) The models of D1-SPD and D2-SPD. The active sites were displayed as an electrostatic surface. (C and D) The important residues in the active sites of two complexes and SPD were rendered in stick representation. (E and F) Schematic depiction of the main interactions between SPD with D1 and D2.
FIGURE 7
FIGURE 7
Energy barrier between the agonistic and antagonistic conformers of SPD calculated with B3LYP/6311g**. The calculated energy is 1.55 kcal/mol after the zero-point vibrational energy (ZPVE) correction.
FIGURE 8
FIGURE 8
Time-dependent Rg of the four models. (A) D1 and D1-SPD. (B) D2 and D2-SPD.
FIGURE 9
FIGURE 9
Largest anharmonic motions of the TM helices (viewed intracellularly) identified by essential dynamics analysis. (A) D1-SPD. (B) D2-SPD. For comparison, the minimum motion of helices is shown in green, and the maximum is colored in purple for both complexes.
FIGURE 10
FIGURE 10
Signal transduction model of the D1 receptor by an SPD-like agonist. R represents the dynamic state, Rt1 and Rt2 are transitional states before receptor activation, and R* refers to the activated state ready to couple with intracellular G-proteins.
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