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D1 Agonist and D2 Antagonist Dual Effect of SPD FIGURE ns of the DI (A)and D2 (B)receptor during the open-closed process of the inding site as observed from MD simu- lations. a dashed arrow line indicates the position of the"mouth, and a double dashed line shows the*"mouth 緲嚕輬 pening. All of the conformations are hown in the style of molecular surfa plored by electrostatic potential. The ed color stands for negative electrostatic candidates of DRs were identified from each of the MD Dual action mechanism of SPD with dopamine rajectories of the unliganded DI and D2 receptors(dotted D1 and D2 receptors lines in Fig. 2)with two criteria: lower potential energy and The structural determinant of pharmacological specificity obvious geometrical difference among different conforma- of SPD ons. Then spd was docked into the binding cavities of these 10 conformations of each receptor and the binding The dynamics of the interactions between SPD and DI or d2 energies were estimated by means of Auto Dock3.05(37). was investigated to understand the agonistic and antagonistic Both the binding mode and binding affinity between SPD mechanism of SPD ind DRs were used to guide the selection of the conforma The distances between the key residues in the active sites ion that is most likely to be active. From among 10 were monitored and used to delineate the dynamical change candidates, the conformations were selected as the possible of the active site among the bound complexes. Most dis- conformation candidates if their main binding modes are in tances fluctuate a little bit in complexes SPD-DI. It shows agreement with known mutagenesis experiments. From these that SPD packs well with the side chains of residues in the possible conformation candidates, the conformation having binding cavity of DI. In the SPD-D2 complex, there is an the lowest binding energy toward SPD was selected as the interesting conformational change around the ligand. The conformations most likely to be active for each DR. The side chains of F-6.52 and H-6.55 come near the aromatic predicted lowest binding free energy of SPD for Dl is.8 rings A and D of SPD, apparently induced by hydrophobic kcal/mol and.7 kcal/mol, respectively. Although there interactions among these groups and the bending of rings A are deviations between the experimental value(-10.8 kcal/ and d toward side chains of F-6.52 and H-6.55. There is also mol and.6 kcal/mol)(42-45)and predicted data, the an electrostatic attraction between the protonated side chain general trend observed in predicated binding free energies is of H-6.55 and the electron-rich group of ring A and atom that SPd binds to DI more strongly than to D2. The errors in O2 of SPD(Fig. 6 D). The conformational bending of SPD predicting binding affinities mainly come from the homol- and the aromatic packing with the side chains of F-6.52 ogy models of DRs and the imperfect empirical parameters and H-6.55 appear to hold SPD against helix VI, constrain- in AutoDock 3.05 for estimating binding affinity ing it after SPD binding. In comparison, there is no such E Away FIGURE 4 Distance fluctuations during the MD simulations. (A)Distance from Na B他 of K-167(EL-2)to Cs of E-302(EL-3)of the DI receptor; (B)distance from Cy of 08 D-178(EL-2)to the centroid of the are 6H matic side chain of Y-408(EL-3)of the D2 04 receptor. The open and closed conforma- state open state tions in Fig 3 are shown in the dotted lines me("0 800010000 200040006000080001000inhg.2. B Biophysical Joumal 93(5)1431-1441candidates of DRs were identified from each of the MD trajectories of the unliganded D1 and D2 receptors (dotted lines in Fig. 2) with two criteria: lower potential energy and obvious geometrical difference among different conforma￾tions. Then SPD was docked into the binding cavities of these 10 conformations of each receptor and the binding energies were estimated by means of AutoDock3.05 (37). Both the binding mode and binding affinity between SPD and DRs were used to guide the selection of the conforma￾tion that is most likely to be active. From among 10 candidates, the conformations were selected as the possible conformation candidates if their main binding modes are in agreement with known mutagenesis experiments. From these possible conformation candidates, the conformation having the lowest binding energy toward SPD was selected as the conformations most likely to be active for each DR. The predicted lowest binding free energy of SPD for D1 is 12.8 kcal/mol and 11.7 kcal/mol, respectively. Although there are deviations between the experimental value (10.8 kcal/ mol and 9.6 kcal/mol) (42–45) and predicted data, the general trend observed in predicated binding free energies is that SPD binds to D1 more strongly than to D2. The errors in predicting binding affinities mainly come from the homol￾ogy models of DRs and the imperfect empirical parameters in AutoDock 3.05 for estimating binding affinity. Dual action mechanism of SPD with dopamine D1 and D2 receptors The structural determinant of pharmacological specificity of SPD The dynamics of the interactions between SPD and D1 or D2 was investigated to understand the agonistic and antagonistic mechanism of SPD. The distances between the key residues in the active sites were monitored and used to delineate the dynamical change of the active site among the bound complexes. Most dis￾tances fluctuate a little bit in complexes SPD-D1. It shows that SPD packs well with the side chains of residues in the binding cavity of D1. In the SPD-D2 complex, there is an interesting conformational change around the ligand. The side chains of F-6.52 and H-6.55 come near the aromatic rings A and D of SPD, apparently induced by hydrophobic interactions among these groups and the bending of rings A and D toward side chains of F-6.52 and H-6.55. There is also an electrostatic attraction between the protonated side chain of H-6.55 and the electron-rich group of ring A and atom O2 of SPD (Fig. 6 D). The conformational bending of SPD and the aromatic packing with the side chains of F-6.52 and H-6.55 appear to hold SPD against helix VI, constrain￾ing it after SPD binding. In comparison, there is no such FIGURE 3 Representative conforma￾tions of the D1 (A) and D2 (B) receptors during the open-closed process of the binding site as observed from MD simu￾lations. 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 Distance fluctuations during the MD simulations. (A) Distance from Nz of K-167 (EL-2) to Cd of E-302 (EL-3) of the D1 receptor; (B) distance from Cg of D-178 (EL-2) to the centroid of the aro￾matic side chain of Y-408 (EL-3) of the D2 receptor. The open and closed conforma￾tions in Fig. 3 are shown in the dotted lines in Fig. 2. D1 Agonist and D2 Antagonist Dual Effect of SPD 1435 Biophysical Journal 93(5) 1431–1441
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