Table 3. Protein Folding Variation Matrix (PFVM) for protein of Human cellular tumor antigen p53 (P53_HUMAN). Top section: the sequence of 393 of amino acids of P53_HUMAN with numeric ruler. Section below sequence: the PFVM. The PFSC letters in each vertical column represent the local folding variation for 5 successive amino acids along sequence. The order of PFSC letters in each vertical column is ranked from higher to lower according the frequency numbers of folding shapes in PDB. The PFSC letters are marked by colors: red is for typical helix fold; blue for typical beta fold; pink and light blue for folds with partial helix or beta; black for irregular folds. Bottom section showed the disorder determined by PDB.
The PFVM has capability to discover the change of local folding conformation caused by mutation, even if 3D structural data is lacked. The P53 has an important role as a tumor suppressor, but the mutations severely compromise the tumor suppression. The mutations may happen in various positions or make different substitution in same position of sequence related to different diseases and biological functions. The different substitution of amino acid residue 183 of P53, for example, related to different biological functions. The mutation S183E abolishes phosphorylation, but the mutation S183A inhibits its transcriptional activity.17 The replacement of amino acid residue triggered the changes of folding conformation. The changes of local folding shapes around residue 183 of P53_HUMAN are revealed by PFVM and the results are exhibited in Table 4. The mutation on a residue primarily affects around five columns of local folding variations in PFVM which are highlighted with a yellow color. It is apparent that with comparison of native state, the folding patterns are changed and the numbers of folding variations are reduced respectively after mutating S183E and S183A in P53 sequence. The change of conformation, which is caused by a residue replacement in mutation, is hard to be observed by experimental measurements, such as NMR, X-ray crystallography or Cryo-electron microscopy, and it is hard to be compared by the results from computational molecule dynamics simulation. However, the PFVM provided a useful means to reveal the difference of folding conformation between before and after mutation. Additionally, the folding conformation changes in PFVM caused by mutation are further demonstrated that the protein folding was associated with the order of amino acids in sequence.