Molecular structure and dynamics of serotonin.

The electronic structure and low-energy conformations of the protonated serotonin molecule were examined by quantum mechanical and molecular mechanical calculations based on the AMBER force field. The flexibility and internal motions of the molecule, which may be important for its mode of receptor interaction, were examined by molecular dynamics simulations in vacuo and in aqueous solution. Two crystal structures and four computed serotonin structures were used as starting points in the calculations. Both gauche and anti conformers were observed during molecular dynamics simulations in aqueous solution, but only gauche conformers of serotonin were observed in vacuo. The simulations demonstrated that the side chain conformation may adjust in order to fit into a receptor binding site. Energy refined gauche conformers had lowest molecular energies both in vacuo and in aqueous solution. Ab initio molecular electrostatic potentials were calculated in 4 layers surrounding the molecule and projected into net atomic point charges. The effect of the hydroxyl group in lowering the molecular electrostatic potentials around the phenyl ring was highly dependent on the conformation of the side chain. Conformers with an extended side chain had significantly lower electrostatic potentials over the phenyl ring than those with a folded conformation.