Searching the ?biologically relevant?conformation of dopamine. A Computational approach.

ANDUJAR, SEBASTIAN; TOSSO, RODRIGO; SUVIRE, FERNANDO; ANGELINA, EMILIO; PERUCHENA, NELIDA; CABEDO, NURIA; CORTES, DIEGO; ENRIZ, RICARDO

JOURNAL OF CHEMICAL INFORMATION AND MODELING

AMER CHEMICAL SOC

Año: 2012 vol. 52 p. 99 - 112

1549-9596

We report here an exhaustive and complete conformational study on the conformational potential energy hypersurface (PEHS) of dopamine (DA) interacting with the dopamine D2 receptor (D2-DR). A reduced 3D model for the binding pocket of the human D2-DR was constructed based on the theoretical model structure of bacteriorhodopsin. In our reduced model system, only 13 aminoacids were included to perform the quantum mechanics calculations. To obtain the different complexes of DA/D2-DR, we combined semiempirical (PM6), DFT (B3LYP/6-31G(d)) and QTAIM calculations. The molecular flexibility of DA interacting with the D2-DR was evaluated from potential energy surfaces and potential energy curves. A comparative study between the molecular flexibility of DA in gas phase and at the D2-DR was carried out. In addition several molecular dynamics simulations were carried out to evaluate the molecular flexibility of the different complexes obtained. Our results allow us to postulate the complexes type A as the ?biologically relevant conformations? of DA. In addition the theoretical calculations reported here suggested that a mechanistic stepwise process take place for DA in which the protonated nitrogen group (in any conformation) acts as the anchoring portion, and this process is followed by a rapid rearrangement of the conformation allowing the interaction of the catecholic OH groups.