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

LUISA GOICOCHEA MORO; RODRIGO TOSSO; PARRAVICINI, OSCAR; NATALIA ZARYCZ; ANGELINA, EMILIO; ANDUJAR, SEBASTIAN; ENRIZ, RICARDO DANIEL

San Luis

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

Sociedad Argentina de Biofísica-UNSL

Understanding of the biological behavior ofdifferent L-R complexes requires determines the conformational and electronicaspects of both the small ligand as well as the binding site of its receptor.Here we report the conformational and electronic behavior of dopamine (DO)interacting at the active site of the D2 dopamine receptor (D2DR).The selectionof this molecular target and the ligands is due to two main reasons: it is amolecular target of great importance for medicinal chemistry and it has recentlybeen crystallized and therefore it has very important recent structuralinformation. Different computational techniques have been used in combinationin this study. In this way docking calculations, molecular dynamics simulationsand quantum mechanical calculations have been used. The different molecularinteractions of the complexes were evaluated in detail using two techniques:QTAIM and NMR nuclear magnetic shielding constants calculations.Our study goes much further than any previouslydone, since for the first time we have been able to obtain and report thecomplete conformational potential energy surfaces for these ligands in theirrespective pockets of union. Analysis of the complete PES is the mostcomprehensive way to understand the conformational behavior of a ligand such asdopamine (two rotatable bonds), since it is possible to locate all criticalpoints on the surface and even see their different conformationalinter-conversion paths. Our study indicates that there are sevendifferent conformations of DO as the most relevant. Of these seven, two arethose that could be considered as the biologically relevant conformations ofDO. The most important molecular interactions that stabilize these molecularcomplexes are those with Asp80, Ser159, Ser160, Ser163, Phe164 and Val81, Cys84,Thr85 and Tyr403.