Estimation of structural similarity of membrane proteins by hydropathy profile alignment.

Many membrane proteins consist of bundles of alpha-helices that are reflected in typical hydropathy profiles of the amino acid sequences. The profiles provide a link between the amino acid sequence of the polypeptide chain and its folding and are much better conserved during evolution than the amino acid sequences from which they are deduced. In this paper, the hydropathy profiles are used to compare structures of membrane proteins or families of membrane proteins. A technique is proposed that computes the optimal alignment of hydropathy profiles without making use of the underlying sequences. The results show that two membrane proteins with only marginal sequence identity or two non-related families of membrane proteins can have very similar hydropathy profiles, indicating similar global structures. Two parameters are defined that measure differences between hydropathy profiles. The Structure Divergence Score (SDS) provides a measure for the divergence in profiles that reflect one and the same global structure. The SDS is derived from the individual hydropathy profiles of the members of a homologous protein family that are believed to share the same structure. The Profile Difference Score (PDS) quantifies the difference between two hydropathy profiles. Comparison of the PDS of the optimal alignment of the hydropathy profiles of two families of membrane proteins with the SDSs of the two families provides a criterion for structural similarity. Using this technique, pairwise alignment of the family profiles of eight families of secondary transporters suggests that the families fall into four structural classes.