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Molecular dynamics simulations and docking studies on 3D models of the heterodimeric and homodimeric 5-HT(2A)
Agostino Bruno1, Claudia Beato, Gabriele Costantino
1Dipartimento Farmaceutico, Via G. P. Usberti 27/A, Campus Universitario, Università degli Studi di Parma, 43100 Parma, Italy.
Background:
G-protein coupled receptors may exist as functional homodimers, heterodimers and even as higher aggregates. In this work, we investigate the 5-HT(2A) receptor, which is a known target for antipsychotic drugs. Recently, 5-HT(2A) has been shown to form functional homodimers and heterodimers with the mGluR2 receptor. The objective of this study is to build up 3D models of the 5-HT(2A)/mGluR2 heterodimer and of the 5-HT(2A)-5-HT(2A) homodimer, and to evaluate the impact of the dimerization interface on the shape of the 5-HT(2A) binding pocket by using molecular dynamics simulations and docking studies.
Results And Discussion:
The heterodimer, homodimer and monomeric 5-HT(2A) receptors were simulated by molecular dynamics for 40 ns each. The trajectories were clustered and representative structures of six clusters for each system were generated. Inspection of the these representative structures clearly indicate an effect of the dimerization interface on the topology of the binding pocket. Docking studies allowed to generate receiver operating characteristic curves for a set of 5-HT(2A) ligands, indicating that different complexes prefer different classes of 5-HT(2A) ligands.
Conclusion:
This study clearly indicates that the presence of a dimerization interface must explicitly be considered when studying G-protein coupled receptors known to exist as dimers. Molecular dynamics simulation and cluster analysis are appropriate tools to study the phenomenon.
