Sequence and structure patterns in proteins from an analysis of the shortest helices: implications for helix nucleation

Abstract

The shortest helices (three-length 3₁₀ and four-length α), most abundant among helices of different lengths, have been analyzed from a database of protein structures. A characteristic feature of three-length 3₁₀-helices is the shifted backbone conformation for the C-terminal residue (φ,ψ angles: -95°,0°), compared to the rest of the helix (-62°,-24°). The deviation can be attributed to the release of electrostatic repulsion between the carbonyl oxygen atoms at the two C-terminal residues and further stabilization (due to a more linear geometry) of an intrahelical hydrogen bond. A consequence of this non-canonical C-terminal backbone conformation can be a potential origin of helix kinks when a 3₁₀-helix is sequence-contiguous at the α-helix N-terminal. An analysis of hydrogen bonding, as well as hydrophobic interactions in the shortest helices shows that capping interactions, some of them not observed for longer helices, dominate at the N termini. Further, consideration of the distribution of amino acid residues indicates that the shortest helices resemble the N-terminal end of α-helices rather than the C terminus, implying that the folding of helices may be initiated at the N-terminal end, which does not get propagated in the case of the shortest helices. Finally, pairwise comparison of ?-turns and the shortest helices, based on correlation matrices of site-specific amino acid composition, and the relative abundance of these short secondary structural elements, leads to a helix nucleation scheme that considers the formation of an isolated β-turn (and not an β-turn) as the helix nucleation step, with shortest 3₁₀-helices as intermediates between the shortest α-helix and the β-turn. Our results ascribe an important role played by shortest 3₁₀-helices in proteins with important structural and folding implications.