Structural-dynamic insights into the <i>H. pylori</i> cytotoxin-associated gene A (CagA) and its abrogation to interact with the tumor suppressor protein ASPP2 using decoy peptides

Abstract

<i>Helicobacter pylori</i> (<i>H. pylori</i>) is one of the most extensively studied Gram-negative bacteria due to its implication in gastric cancer. The oncogenicity of <i>H. pylori</i> is associated with cytotoxin-associated gene A (CagA), which is injected into epithelial cells lining the stomach. Both the <i>C</i>- and <i>N</i>-termini of CagA are involved in the interaction with several host proteins, thereby disrupting vital cellular functions, such as cell adhesion, cell cycle, intracellular signal transduction, and cytoskeletal structure. The <i>N</i>-terminus of CagA interacts with the tumor-suppressing protein, apoptosis-stimulating protein of p53 (ASPP2), subsequently disrupting the apoptotic function of tumor suppressor gene p53. Here, we present the in-depth molecular dynamic mechanism of the CagA-ASPP2 interaction and highlight hot-spot residues through <i>in silico</i> mutagenesis. Our findings are in agreement with previous studies and further suggest other residues that are crucial for the CagA-ASPP2 interaction. Furthermore, the ASPP2-binding pocket possesses potential druggability and could be engaged by decoy peptides, identified through a machine-learning system and suggested in this study. The binding affinities of these peptides with CagA were monitored through extensive computational procedures and reported herein. While CagA is crucial for the oncogenicity of <i>H. pylori</i>, our designed peptides possess the potential to inhibit CagA and restore the tumor suppressor function of ASPP2.