A MATHEMATICALLY DEFINED MOTIF FOR THE RADIAL-DISTRIBUTION OF CHARGEDRESIDUES ON APOLIPOPROTEIN AMPHIPATHIC ALPHA-HELIXES

Multiple amphipathic alpha-helical candidate domains have been identif ied in exchangeable apolipoproteins by sequence analysis and indirect experimental evidence. The distribution of charged residues can differ within and between these apolipoproteins. Segrest et al. (Segrest, J. P., H. DeLoof, J. G. Dohlman, C. G. Brouillette, and G. M. Anantharam aiah. 1990. Proteins. 8:103-117.) argued that these differences are co rrelated with lipid affinity. A mathematically defined motif for the p articular charge distribution associated with high lipid affinity (cla ss A) is proposed. Primary sequence data from protein segments propose d previously to have an amphipathic a-helical structure are scanned. C ounting formulas are presented for determining the conditional probabi lity that the match between an observed charge distribution and the pr oposed motif would occur by chance. Because the preselected helical se gments are short (the modal length is 22) and the motif definition imp oses multiple constraints on the acceptable distributions, the compute r-based algorithm is quite feasible computationally. 19 of the 20 segm ents previously assigned to class A match the motif sufficiently well (the remaining one is borderline), while very few others ''erroneously '' pass the screening test. These results confirm the original assignm ents of the candidate domains and, thus, support the hypothesis that t here is a distinguishable subset of helixes having high lipid affinity . This counting approach is applicable to a growing subset of protein sequence analysis problems in which the segment lengths are short and the motif is complex.