D1 corresponds to all residues with RSA > 7%. The remaining inaccessible residues were categorised into the D2 and D3. For the case of packing (A–C), D2 and D3 corresponds to residue packing values ≤0.56 and >0.56, respectively. For depth (D–F), D2 and D3 corresponds to residue depth values ≤6 and >6 Å, respectively. Residue conservation with packing and depth were analysed for residues grouped on the basis of polar, charged and hydrophobic properties. Residue conservations were obtained from the substitution tables calculated using the ULLA program [58]. Ulla uses structural alignment of protein families annotated by the program JOY, indicating the local conformation and side-chain environment [54] for the purpose of calculating substitution tables.