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

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Biophysics

Background:

• Serotonin (5-hydroxytryptamine, 5-HT) is a crucial neurotransmitter.
• Understanding 5-HT's conformational flexibility is key to its function.

Purpose of the Study:

• To investigate the stable conformers of serotonin using quantum chemistry.
• To analyze the intramolecular forces governing these conformations.

Main Methods:

• Adiabatic conformational analysis using quantum chemistry.
• Vibrational frequency analysis.
• Atoms in Molecules (AIM), Natural Bond Orbital (NBO) analyses.
• Time-Dependent Density Functional Theory (TDDFT) for spectra.
• Energy Decomposition Analysis (EDA).

Main Results:

• Six stable conformers of 5-HT identified based on dihedral angles.
• Intramolecular nonbonded interaction and charge-transfer observed in specific conformers (GmGp, GmGm).
• Cation-π interactions confirmed, driven by electrostatic and charge-transfer terms.
• Conformer stability differences attributed to exchange repulsion and polarization.

Conclusions:

• Intramolecular forces, especially cation-π interactions, significantly influence 5-HT's conformational landscape.
• These interactions affect electronic distribution and bond characteristics.
• The study provides insights into the molecular basis of 5-HT's conformational behavior.