Innovative high-performance computing approaches for molecular neuromedicine

RWTH Publications (RWTH Aachen)

Abstract

G protein-coupled receptors (GPCRs) are integral membrane protein characterized by a seven transmembrane scaffold. They are involved in the regulation of several cellular downstream pathways, and they are the target of more than one third of the current available drugs on the market. Among GPCRs, dopamine D2 represents the main target of both first- and second-generation antipsychotic drugs used to treat several neurological disorders, such as schizophrenia and Parkinson’s disease. In cells, D2 can exist as a monomer, dimer, or higher-order oligomer. The presence of agonists or antagonists affects dimer formation; in particular, the proportion of D2 dimers increases from approximately30% to 45% upon agonist activation. To date, no experimental structural information on D2 dimers has been available. Here, I developed a computational protocol that combines coarse-grained molecular dynamics simulations based on the Martini 3 force field combined with well-tempered metadynamics enhanced sampling to predict the structural determinants of D2 dimerization. My simulations are consistent with experimental observations and show that the protocol is sensitive not only to the activation state of the receptors, but also to the lipid membrane composition, which plays a crucial role in receptor signaling and membrane transport. This approach can naturally be extended to D2 hetero-oligomers and other membrane protein complexes, such as those involving the adenosine A2 receptor, with which it shares an intimate interaction. Overall, my results provide a structural framework and a computational strategy that may serve as a solid basis for structure-based drug design targeting membrane receptor complexes.

Authors 1

1. Alessandro Marchetto corresponding Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen