Information Transfer in Active States of Human β2-Adrenergic Receptor via Inter-Rotameric Motions of Loop Regions

Abstract

Two independent 1.5 μs long MD simulations were conducted for the fully atomistic model of the human beta2-adrenergic receptor (β2AR) in a complex with a G protein to investigate the signal transmission in a fully active state via mutual information and transfer entropy based on α-carbon displacements and rotameric states of backbone and side-chain torsion angles. Significant correlations between fluctuations in α-Carbon displacements were mostly detected between transmembrane (TM) helices, especially TM5 and TM6 located at each end of ICL3 and TM7. Signal transmission across β2-AR was quantified by shared mutual information; a high amount of correspondence was distinguished in almost all loop regions when rotameric states were employed. Moreover, polar residues, especially Arg, made the most contribution to signal transmission via correlated side-chain rotameric fluctuations as they were more frequently observed in loop regions than hydrophobic residues. Furthermore, transfer entropy identified all loop regions as major entropy donor sites, which drove future rotameric states of torsion angles of residues in transmembrane helices. Polar residues appeared as donor sites from which entropy flowed towards hydrophobic residues. Overall, loops in β2AR were recognized as potential allosteric hot spot regions, which play an essential role in signal transmission and should likely be used as potential drug targets.