Investigation of serotonin-receptor interactions, stability and signal transduction pathways via molecular dynamics simulations

Arunima Verma; Padmabati Mondal

doi:10.1016/j.bpc.2024.107386

Investigation of serotonin-receptor interactions, stability and signal transduction pathways via molecular dynamics simulations

Biophys Chem. 2024 Dec 27:318:107386. doi: 10.1016/j.bpc.2024.107386. Online ahead of print.

Authors

Arunima Verma¹, Padmabati Mondal²

Affiliations

¹ Department of Chemistry, Indian Institute of Science, Education and Research (IISER) Tirupati Yerpedu Mandal, Tirupati 517619, India.
² Department of Chemistry and Center for Atomic, Molecular, Optical Sciences and Technologies (CAMOST), Indian Institute of Science, Education and Research (IISER) Tirupati, Yerpedu Mandal, Tirupati 517619, India. Electronic address: padmabati.mondal@iisertirupati.ac.in.

PMID: 39756217
DOI: 10.1016/j.bpc.2024.107386

Abstract

Serotonin-receptor binding plays a key role in several neurological and biological processes, including mood, sleep, hunger, cognition, learning, and memory. In this article, we performed molecular dynamics simulation to examine the key residues that play an essential role in the binding of serotonin to the G-protein-coupled 5-HT_1B receptor (5HT_1BR) via electrostatic interactions. Key residues for electrostatic interactions were identified via bond distance analysis and frustration analysis methods. An end-point free energy calculation method determines the stability of the 5-HT_1BR due to serotonin binding. The single-point mutation of the polar/charged amino acid residues (Asp129, Thr134) on the binding sites and the calculation of binding free energy validate the quantitative contribution of these residues to the stability of the serotonin-receptor complex. The principal component analysis reflects that the serotonin-bound 5-HT_1BR is more stabilized than the apo-receptor regarding dynamical changes. The difference dynamic cross-correlations map shows the correlation between the transmembranes and mini-G_o, which indicates that the signal transduction happens between mini-G_o and the receptor. Allosteric pathway analysis reveals the key nodes and key pathways for signal transduction in 5-HT_1BR. These results provide useful insights into the study of signal transduction pathways and mutagenesis to regulate the binding and functionality of the complex. The developed protocols can be applied to study local non-covalent interactions and long-range allosteric communications in any protein-ligand system for computer-aided drug design.

Keywords: Allosteric pathway; Binding free energy; Electrostatic interactions; Molecular dynamics simulation; Serotonin-receptor binding; Signal transduction.