Structural models and Sort-seq data for: Packing of apolar amino acids is not a strong stabilizing force in transmembrane helix dimerization

The factors that stabilize the folding and oligomerization of membrane
proteins are still not well understood. In particular, it remains unclear
how the tight and complementary packing between apolar side chains
observed in the core of membrane proteins contributes to their stability.
Complementary packing is a necessary feature since packing defects are
generally destabilizing for membrane proteins. The question is the extent
to which packing of apolar side chains – and the resulting van der Waals
interactions – is a sufficient driving force for stabilizing the
interaction between transmembrane helices in the absence of hydrogen
bonding and polar interactions. We addressed this question with an
approach based on high-throughput protein design and the homodimerization
of single-pass helices as the model system. We designed hundreds of
transmembrane helix dimers mediated by apolar packing in the backbone
configurations that are most commonly found in membrane proteins. We
assessed the association propensity of the designs in the membrane of
Escherichia coli and found that they were most often monomeric or, at
best, weakly dimeric. Conversely, a set of controls designed in the
backbone configuration of the GASright motif, which is mediated by weak
hydrogen bonds, displayed significantly higher dimerization propensity.
The data suggest that packing of apolar side chains and van der Waals
interactions are a relatively weak force in driving transmembrane helix
dimerization. It also confirms that GASright is a special configuration
for achieving stability in membrane proteins.