Structural Determinants of Transmembrane β-Barrels

The recognition of β-barrel membrane proteins based on their sequence is more challenging than the recognition of α-helical membrane proteins. This goal could benefit from a better understanding of the physical determinants of transmembrane β-barrel structure. To that end, we first extend the IMM1 implicit membrane model in a way that allows the modeling of membrane proteins with an internal aqueous pore. The new model (IMM1-pore) gives stable molecular dynamics trajectories for three β-barrel membrane proteins of different sizes and negative water-to-membrane transfer energies of reasonable magnitude. It also discriminates the correct fold for a pair of 10-stranded and 12-stranded transmembrane β-barrels. We then consider a pair of β-barrel proteins:  OmpA, which is a membrane β-barrel with hydrophobic residues on the exterior and polar residues in the interior, and retinol binding protein, which is a water soluble protein with polar residues on the exterior and hydrophobic residues in the interior. By threading the sequence of one onto the structure of the other we make two pairs of structures for each sequence, one native and the other a decoy, and evaluate their energy. The energy function discriminates the correct structure. By decomposing the energy into residue contributions we examine which features of each sequence make it fold into one or the other structure. It is found that for the OmpA sequence the largest contribution to stability comes from interactions between polar residues in the interior of the barrel. The major factor that prevents the retinol binding protein sequence from adopting a transmembrane fold is the presence of polar/charged residues at the edges of the putative transmembrane β-strands as well as the less favorable interior polar residue interactions. These results could help design simplified scoring functions for fold recognition and structure prediction of transmembrane β-barrels.