ct9b01136_si_001.pdf (2.07 MB)
Characterizing Interhelical Interactions of G‑Protein Coupled Receptors with the Fragment Molecular Orbital Method
journal contribution
posted on 2020-03-09, 15:37 authored by Alexander Heifetz, Inaki Morao, M. Madan Babu, Tim James, Michelle W. Y. Southey, Dmitri G. Fedorov, Matteo Aldeghi, Michael J. Bodkin, Andrea Townsend-NicholsonG-protein coupled receptors (GPCRs)
are the largest superfamily
of membrane proteins, regulating almost every aspect of cellular activity
and serving as key targets for drug discovery. We have identified
an accurate and reliable computational method to characterize the
strength and chemical nature of the interhelical interactions between
the residues of transmembrane (TM) domains during different receptor
activation states, something that cannot be characterized solely by
visual inspection of structural information. Using the fragment molecular
orbital (FMO) quantum mechanics method to analyze 35 crystal structures
representing different branches of the class A GPCR family, we have
identified 69 topologically equivalent TM residues that form a consensus
network of 51 inter-TM interactions, providing novel results that
are consistent with and help to rationalize experimental data. This
discovery establishes a comprehensive picture of how defined molecular
forces govern specific interhelical interactions which, in turn, support
the structural stability, ligand binding, and activation of GPCRs.