Conformational and Electronic Intricacies of Dopamine Interacting with the D2 Dopamine Receptor. A Comprehensive Theoretical Study

PARRAVICINI, OSCAR; VETORAZZI, MARCELA ; TOSSO, RODRIGO D.; ANGELINA, EMILIO ; ENRIZ, RICARDO D. ; GOICOECHEA MORO, LUISA; M. NATALIA C. ZARYCZ; ANDUJAR, SEBASTIAN

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Sociedad Argentina de Biofísica

Understanding of the biologicalbehavior of different L-R complexes requires determining the conformational andelectronic aspects of both the small ligand as well as the binding site of itsreceptor. Here we report the conformational and electronic behavior of dopamine(DO) interacting at the active site of the D2 dopamine receptor (D2DR). Theselection of this molecular target is due to two main reasons: it is amolecular target of great importance for medicinal chemistry and very useful structuralinformation has been recently reported due to the D2DR has been crystallized. Differentcomputational techniques have been used in combination in this study. In thisway, docking calculations, molecular dynamics simulations and quantum mechanicalcalculations have been performed. Moreover, the different molecularinteractions of the complexes were evaluated in detail using two techniques:QTAIM (Quantum Theory of Atoms in Molecules) and NMR nuclear magnetic shieldingconstants calculations.Our study goes much further than anypreviously done, since for the first time we have been able to obtain andreport the complete conformational potential energy surface (PES) for DO in itsbinding pocket. Analysis of the complete PES is the most comprehensive way tounderstand the conformational behavior of a ligand such as DO, which possessestwo rotatable bonds, since it is possible to locate all critical points on thesurface and even see its different conformational inter-conversion paths. Our study indicates that sevendifferent conformations of DO are the most relevant. From these seven ones, twoare those that could be considered as the biologically relevant conformationsof DO. On the other hand, the most important molecular interactions thatstabilize these molecular complexes are those with Asp80, Val81, Cys84, Thr85, Ser159,Ser160, Ser163, Phe164 and Tyr403.