A comprehensive computational study of amino acid interactions in membrane proteins.

Transmembrane proteins play a fundamental role in a wide series of biological processes but, despite their importance, they are less studied than globular proteins, essentially because their embedding in lipid membranes hampers their experimental characterization. In this paper, we improved our understanding of their structural stability through the development of new knowledge-based energy functions describing amino acid pair interactions that prevail in the transmembrane and extramembrane regions of membrane proteins. The comparison of these potentials and those derived from globular proteins yields an objective view of the relative strength of amino acid interactions in the different protein environments, and their role in protein stabilization. Separate potentials were also derived from α-helical and β-barrel transmembrane regions to investigate possible dissimilarities. We found that, in extramembrane regions, hydrophobic residues are less frequent but interactions between aromatic and aliphatic amino acids as well as aromatic-sulfur interactions contribute more to stability. In transmembrane regions, polar residues are less abundant but interactions between residues of equal or opposite charges or non-charged polar residues as well as anion-π interactions appear stronger. This shows indirectly the preference of the water and lipid molecules to interact with polar and hydrophobic residues, respectively. We applied these new energy functions to predict whether a residue is located in the trans- or extramembrane region, and obtained an AUC score of 83% in cross validation, which demonstrates their accuracy. As their application is, moreover, extremely fast, they are optimal instruments for membrane protein design and large-scale investigations of membrane protein stability.