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.