Theoretical Conformational Analysis for Neurotransmitters in the Gas Phase and in Aqueous Solution. Serotonin.

Conformational analyses have been performed for protonated serotonin in the gas phase, aqueous solution, and in the binding cavity of a 5-HT2A receptor model. DFT geometry optimizations have been performed in the gas phase at the B3LYP/6-31G* levels. Optimized calculations up to the B3LYP/6-311++G** level find two low-energy gauche conformations separated by 8-10 kcal/mol barriers from a trans conformation with relative energy of about 6 kcal/mol. In aqueous solution as concluded from IEF-PCM/B3LYP/6-31G* and IEF-PCM/MP2/6-31G*//IEF-PCM/B3LYP/6-31G* continuum solvent calculations as well as Monte Carlo free energy perturbation simulations with explicit solvent molecules, those barriers decrease to 2-7 kcal/mol, while the two gauche and one trans conformers are within a 3 kcal/mol relative free energy range. The solute is strongly hydrated by about three water molecules around the -NH3(+) group and by one water molecule for each of the pyrrole and phenolic hydrogen atoms. Docking studies of the protonated ligand predicted both gauche and trans ligand conformers to favorably interact with the 5-HT2A receptor in its hypothesized binding cavity. The theoretical studies confirm the experimental results regarding strong interactions with the Asp155 and Ser159 residues (TM helix III) and the interactions of the indole ring with Phe, Trp, and Tyr side chains in TM V, VI, and VII helices within a 24 kcal/mol range for the relative interaction energies.