In silico decryption of serotonin–receptor binding: local non-covalent interactions and long-range conformational changes

Serotonin–receptor binding is the key step in the process behind serotonin functionality, including several psychological and physiological behaviours. This study is focused on identifying the main non-covalent interactions controlling the stability of serotonin–receptor complexes as well as the main conformational changes in the receptor due to serotonin–receptor binding using classical molecular dynamics simulations and quantum chemical calculations. A qualitative analysis based on two order parameters ((i) the centre of mass distance and (ii) the angle between the surface normals of each aromatic residue and serotonin in the binding site) on the serotonin–receptor complex trajectory suggests that the T-type stacking interaction is predominant in the binding site. Quantum chemical calculations of the stacking interaction energy provide the quantitative contributions of important aromatic residues to the stabilization of the complex. Furthermore, a three body stacking interaction (named ‘L’-type) was observed and likely contributes to the stability of the complex. Direct and water-mediated hydrogen bonding between the residues in the binding site and serotonin contributes to the complex stability. Principal component analysis of the molecular dynamics simulation trajectory of the serotonin–receptor complex and the apo-receptor in water indicates that the whole receptor is significantly stabilized due to serotonin binding. An analysis based on the dynamic cross correlation function reflects the strong correlation between trans-membrane (TM)3, TM5, TM6 (containing residues responsible for the stacking interaction and hydrogen bonding) and mini-G(0) which may participate in signal transduction leading to the functionality of serotonin.