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Laboratory of Molecular Biophysics
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Advances in structure determination of membrane proteins enable analysis of the
propensities of amino acids to be located in extra-membrane versus
trans-membrane locations to be performed on the basis of structure and topology
rather than of sequence alone. Using 29 available structures of integral
membrane proteins with resolutions better than 4Å the distributions of amino
acids in the trans-membrane domains were calculated. The results were compared
to analysis based on just the sequences of the same trans-membrane
-helices
and significant differences were found. The distribution of residues between
trans-membrane -helices and 
-strands was also compared. Large hydrophobic
(Phe, Leu, Ile, Val) residues showed a clear preference for the protein
surfaces facing the lipids for -barrels, but in
-helical proteins no such
preference was seen, with these residues equally distributed between the
interior and the surface of the protein. A notable exception to this was
alanine, which showed a slight preference for the interior of -helical
membrane proteins. Aromatic residues were found to follow saddle-like
distributions preferring to be located in the lipid/water interfaces. The
resultant "aromatic belts" were spaced more closely for -barrel than for
-helical membrane proteins. Charged residues could be shown to generally avoid
surfaces facing the bilayer although they were found to occur frequently in the
trans-membrane region of -barrels. Indeed detailed comparison between
-helical and -barrel proteins showed many qualitative differences in residue
distributions. This may suggest that there are differences in the factors
stabilising -barrels in bacterial outer membranes and
-helix bundles in other membranes.
When homology modelling membrane proteins, it is necessary to optimise multiple alignments of similar sequences. The constituent amino-acids of a membrane protein must interact with several different environments - water, lipid and protein. The variability index for a given alignment position (i.e. residue) provides clues as to the nature of the interaction of that residue with its environment. A method has been developed to analyse the correlation between the accessible surface area of amino-acid side-chains, and their variability within a multiple alignment, in order to help produce the best pairwise alignment of a query sequence with that of a template structure.
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