The Journal of Physical Chemistry B Article Scheme 1. Simplification of I-SPD Structure a D1R /-SPD-D1R 71A R3.50 D3.49 d D2R /-SPD-D2R E6.30 90° R3.50 Y3.51 h D3R/-SPD-D3R E6.30 Figure 6. Mechanism for the triple action of A-SPD on DIR, D2R/D3R(a, b, c)Agonistic mechanism of A-SPD on DIR.(d, e, f). Antagonistic mechanism of I-SPD on D2R.(h, i, D) Antagonistic mechanism of -SPD on D3R. (Table S3, entries I and 3). However, no direct hydrogen hydrophobic stacking is expensed for the formation bonding is established by ring D of I-SPD neither in D2R nor in hydrogen bond(see above discussion) D3R. Another key interaction in 1-SPD-D2R and I-SPD-D3R It is also worthy to note that N6. 55 of dir was bonded to D-OH of [-SPD through its side-chain amide omplexes is that the a ring of 1-SPD is involved in carboxyl oxygen, whereas as the counterpart of N6. 55, H6. 55 in energetically favorable edge-to-face aromatic stacking wi D2R and D3R served as a bridge between TM6 and eCl2 F6.51, F6.52, and H6.55(Figure Sb, c), while in I-SPD-DiR, ontributes to the internal structural stability of the 81 dx. dolora/o.021/p30492351 Phys. Chem. B2012116,8121-813(Table S3, entries 1 and 3).18 However, no direct hydrogen bonding is established by ring D of l-SPD neither in D2R nor in D3R. Another key interaction in l-SPD-D2R and l-SPD-D3R complexes is that the A ring of l-SPD is involved in energetically favorable edge-to-face aromatic stacking with F6.51, F6.52, and H6.55 (Figure 5b,c), while in l-SPD-D1R, hydrophobic stacking is expensed for the formation of hydrogen bond (see above discussion). It is also worthy to note that N6.55 of D1R was hydrogen bonded to D-OH of l-SPD through its side-chain amide carboxyl oxygen, whereas as the counterpart of N6.55, H6.55 in D2R and D3R served as a bridge between TM6 and ECL2, it contributes to the internal structural stability of the receptor by Scheme 1. Simplification of l-SPD Structure Figure 6. Mechanism for the triple action of l-SPD on D1R, D2R/D3R. (a, b, c) Agonistic mechanism of l-SPD on D1R. (d, e, f). Antagonistic mechanism of l-SPD on D2R. (h, i, j) Antagonistic mechanism of l-SPD on D3R. The Journal of Physical Chemistry B Article 8127 dx.doi.org/10.1021/jp3049235 | J. Phys. Chem. B 2012, 116, 8121−8130