Sequence symmetry of hydrophobic residues explains the predictability of inverted histone-fold structure.

(A) Hydrophobic interactions (orange) dominate the formation of binding interface of H2A/H2B (colored in green/purple). (B) Protein sequence alignments of histones H2A, H2B and their reversed sequences highlight the symmetrical distribution of hydrophobic residues. Hydrophobic residues are particularly marked. (C) Cartoon schemes illustrate previously proposed histone evolution hypotheses: i) histones may originate from one single helix-strand-helix structural motif HSH; ii) two HSH patterns form one monomer through duplication, differentiation and fusion; iii) domain swapping between two monomers (colored in green and blue) forms a histone-fold structure. (D) The inverted arrangement based on hydrophobic interactions could be an alternative formation of histone-fold structure.