Amino acid distributions in integral membrane protein structures

Advances in structure determination of membrane proteins enable analysis of the propensities of amino acids in extramembrane versus transmembrane loca tions to be performed on the basis of structure rather than of sequence and predicted topology. Using 29 available structures of integral membrane pro teins with resolutions better than 4 Angstrom the distributions of amino ac ids in the transmembrane domains were calculated. The results were compared to analysis based on just the sequences of the same transmembrane alpha -h elices and significant differences were found. The distribution of residues between transmembrane alpha -helices and beta -strands was also compared. Large hydrophobic (Phe, Leu, Ile, Val) residues showed a clear preference f or the protein surfaces facing the lipids for beta -barrels, but in alpha - helical proteins no such preference was seen: with these residues equally d istributed between the interior and the surface of the protein. A notable e xception to this was alanine, which showed a slight preference for the inte rior of alpha -helical membrane proteins. Aromatic residues were found to f ollow saddle-like distributions preferring to be located in the lipid/water interfaces. The resultant 'aromatic belts' were spaced more closely for be ta -barrel than for alpha -helical membrane proteins. Charged residues coul d be shown to generally avoid surfaces facing the bilayer although they wer e found to occur frequently in the transmembrane region of beta -barrels. I ndeed detailed comparison between alpha -helical and beta -barrel proteins showed many qualitative differences in residue distributions. This suggests that there may be subtle differences in the factors stabilising beta -barr els in bacterial outer membranes and alpha -helix bundles in all other memb ranes. (C) 2001 Elsevier Science B.V. All rights reserved.