Cation-π Interactions in Serotonin:  Conformational, Electronic Distribution, and Energy Decomposition Analysis

Abstract

An adiabatic conformational analysis of serotonin (5-hydroxytryptamine, 5-HT) using quantum chemistry led to six stable conformers that can be either +gauche (Gp), -gauche (Gm), and anti (At) depending upon the value taken by ethylamine side chain and 5-hydroxyl group dihedral angles φ1, φ2, and φ4, respectively. Further vibrational frequency analysis of the GmGp, GmGm, and GmAt conformers with the 5-hydroxyl group in the anti position revealed an additional red-shifted N-H stretch mode band in GmGp and GmGm that is absent in GmAt. This band corresponds to the 5-HT side-chain N-H bond involved in an intramolecular nonbonded interaction with the 5-hydroxy indole ring. The influence of this nonbonded interaction on the electronic distribution was assessed by analysis of the spin-spin coupling constants of GmGp and GmGm that show a marked increase for C2-C3 and C8-C9 bonds in GmGm and GmGp, respectively, with a decrease of their double bond character and an increase of their length. The Atoms in Molecules (AIM), Natural Bond Orbital (NBO), and fluorescence and CD spectra (TDDFT method) analyses confirmed the existence in GmGp and GmGm of a through-space charge-transfer between the HOMO and the HOMO-1 π-orbital of the indole ring and the LUMO σ* N-H antibonding orbital of the ammonium group. The strength of the cation-π interaction was determined by calculating binding energies of the NH4(+)/5-hydroxyindole complexes extracted from stable conformers. The energy decomposition analysis indicated that cationic-π interactions in the GmGp and GmGm conformers are governed by the electrostatic term with significant contributions from polarization and charge transfer. The lower stability of the GmGm over the GmGp comes from a higher exchange repulsion and a weaker polarization contributions. Our results provide insight into the nature of intramolecular forces that influence the conformational properties of 5-HT.

New structure of serotonin salt – comparison and conformational analysis of all known serotonin complexes

“…Another remarkable feature is that the conformation of serotonin in the present serotonin adipate structure differs from the most stable conformation predicted for a single molecule by adiabatic conformational analysis using quantum chemistry calculations: a 'free' serotonin molecule in cationic form should be nonplanar (Chothia, 1969;Pratuangdejkul, Jaudon et al, 2006). It also differs from the serotonin conformations in all other known complexes, but the changes are not very significant among the 'flat' conformations.…”

“…In this terminology, the serotonin conformation in the adipate salt is AtAt. The corresponding energy should be about 9 kcal mol À1 (1 kcal mol À1 = 4.184 kJ mol À1 ) greater than that calculated for the most stable GmGp and GpGp conformations predicted for the 'free' molecule in the gas phase (Pratuangdejkul, Jaudon et al, 2006). Three other conformations (GpGp, GmGm and GpAt) were reported for Hirshfeld fingerprint plots for the serotonin molecule in complexes with (left) creatinine sulfate and (right) picrate.…”

“…for creatinine sulfate, picrate and oxalate, respectively. The GmGm and GmGp conformations were presumed to be stabilized by the interaction of the cationic group of serotonin (NH 3 + ) with the -system of the indole ring (Pratuangdejkul, Jaudon et al, 2006). Interestingly, there are no such interactions in the known crystalline forms of serotonin.…”

“…Serotonin adipate has been used in medical formulations in Russia and Eastern Europe as an analogue of serotonin creatinine sulfate monohydrate, but the crystal structure of the adipate salt remained unknown. Another interesting issue is that the conformation of serotonin creatinine sulfate monohydrate is different from that predicted theoretically for a 'free' serotonin molecule in the gas phase (Chothia, 1969;Pratuangdejkul, Jaudon et al, 2006). It was worth investigating whether the conformation of serotonin in the adipate salt is the same as in creatinine sulfate, remembering that they are pharmacological analogues.…”

Effect of pyridyl nitrogen on the conformational landscape of 7-azaserotonin: A computational study

“…The interest in the conformational studies on these large flexible biomolecules has been enhanced by the growing accuracy of quantum mechanical calculations. A great number of theoretical papers treating the conformational landscapes of serotonin and tryptamine have been published [4,5,[7][8][9][10][11] both of which have an ethylamine side chain attached to an indole moiety.…”