masterThesis
Comparação de redes de interação de resíduos (RINs) como uma forma de avaliar a variação conformacional de proteínas
Fecha
2020-06-30Registro en:
FONSECA, Felipe Vieira da. Comparação de redes de interação de resíduos (RINs) como uma forma de avaliar a variação conformacional de proteínas. 2020. 60f. Dissertação (Mestrado em Bioinformática) - Instituto Metrópole Digital, Universidade Federal do Rio Grande do Norte, Natal, 2020.
Autor
Fonseca, Felipe Vieira da
Resumen
Changes in the amino acid sequence may result in alterations in the three-dimensional
protein structure, which may lead to partial or complete loss of function. One way to
represent the chemical interactions between all amino acids in a protein is through the
construction of residue interaction networks (RINs). In RINs, a graph represents the protein
3D structure, with the nodes as amino acid residues, and the edges as the physicochemical
interactions between amino acids. We hypothesize that the comparison between RINs of
the same protein in different conformations can be used to evaluate the effects of mutations
and polymorphisms, as well as for the analysis and validation of theoretical protein models.
Therefore, the present work aimed to build a tool to compare different RINs for a protein and
to use such data to estimate conformational differences between proteins and also validate
models generated by homology modeling. RINs were created using the RING 2.0 (Residue
Interaction Network Generator) program. The tool developed for this purpose, called
Comparator of Residue Interaction Networks (CoRINs), compares all RIN nodes generated
from different structure files (PDBs) of the same protein, taking into account position, chain
and residue, as well as their interactions with the other amino acids. The tool also presents
a plot that estimates the variation of interactions formed by each residue, which we propose
as an estimate for the conformational alterations of that protein site, from a set of compared
PDBs. As a possible application for this tool, we used a dataset with oncogenes and tumor
suppressor genes with their respective reported mutations mapped according to the
connectivity deviation of each residue. Then we retrieved the different conformations for
each resulting protein from a bank of structural conformers and constructed the RINs using
the software RING 2.0 and compared them with CoRINs. The results show that mutations
occurring in the tested oncogenes are more likely to occur in protein sites with a more
significant deviation in the mean number of chemical interactions. Additionally, most of these
genes’ mutations annotated as pathogenic and associated with clinical cancer cases
occurred at sites with the most significant changes in chemical and physical interactions.
These results demonstrate that the CoRINs tool can be useful in identifying non-covalent
interactions essential for protein structure maintenance and in evolutionary studies, such as
in the maintenance of homologous proteins function with high sequence divergence, as well
as for the comparison and validation of theoretical structural models.