The hydrophobicity of the H3 histone fold differs from the hydrophobicity of the other three folds.

The eukaryotic histone dimers, H3-H4 and H2A-H2B, are formed in the cytosol prior to being transported into the nucleus and assembled into the nucleosome. Residue side-chain distances from the interior of the histone dimers are obtained with an ellipsoidal spatial metric and structural information provided by X-ray analyses at atomic resolution of the nucleosome core particles. While the spatial hydrophobic moment profiles of the dimers are comparable with profiles obtained previously that characterize the hydrophobic core of single-chain, single-domain globular soluble proteins, correlation coefficients between the side-chain hydrophobicities and distances from the interior of the H3-H4 dimer and H2A-H2B dimer differ significantly. This difference is traced to the H3 histone fold, which segregates fewer hydrophobic residues within the protein interior than the three other folds. Examination of the correlation coefficient between residue hydrophobicity and side-chain distance from the dimer interior over local regions of the fold sequence shows that the region of reduced correlation is associated mainly with the residues at the carboxyl end of the H3 histone fold, the helical region of the fold involved in the H3-H3' binding of the (H3-H4)(2) tetramer of the nucleosome. Hydrophobic interactions apparently contribute to the binding of this fourfold helical bundle and this evolutionary requirement may trade off against the requirement for H3-H4 dimer stability. The present results provide a different view than previously proposed, albeit of similar origin, to account for the reduced stability of the H3-H4 dimer compared with the H2A-H2B dimer.