Steric restrictions in protein folding: an alpha-helix cannot be followed by a contiguous beta-strand.

Using only hard-sphere repulsion, we investigated short polyalanyl chains for the presence of sterically imposed conformational constraints beyond the dipeptide level. We found that a central residue in a helical peptide cannot adopt dihedral angles from strand regions without encountering a steric collision. Consequently, an alpha-helical segment followed by a beta-strand segment must be connected by an intervening linker. This restriction was validated both by simulations and by seeking violations within proteins of known structure. In fact, no violations were found within an extensive database of high-resolution X-ray structures. Nature's exclusion of alpha-beta hybrid segments, fashioned from an alpha-helix adjoined to a beta-strand, is built into proteins at the covalent level. This straightforward conformational constraint has far-reaching consequences in organizing unfolded proteins and limiting the number of possible protein domains.