Combination of Cα–H Hydrogen Bonds and van der Waals Packing Modulates the Stability of GxxxG-Mediated Dimers in Membranes

The GxxxG motif is frequently found at the dimerization interface of a transmembrane structural motif called GASright, which is characterized by a short interhelical distance and a right-handed crossing angle between the helices. In GASright dimers, such as glycophorin A (GpA), BNIP3, and members of the ErbB family, the backbones of the helices are in contact, and they invariably display networks of 4 to 8 weak hydrogen bonds between Cα–H carbon donors and carbonyl acceptors on opposing helices (Cα–H···O═C hydrogen bonds). These networks of weak hydrogen bonds at the helix–helix interface are presumably stabilizing, but their energetic contribution to dimerization has yet to be determined experimentally. Here, we present a computational and experimental structure-based analysis of GASright dimers of different predicted stabilities, which show that a combination of van der Waals packing and Cα–H hydrogen bonding predicts the experimental trend of dimerization propensities. This finding provides experimenta...