In silico design of DNA aptamers targeting the GGEEF domain to disrupt biofilm-mediated resistance in Vibrio cholerae: a molecular dynamics study

The emergence of multidrug-resistant (MDR) Vibrio cholerae is influenced by chromosomal mutations, gene transfer, and biofilm formation, with the GGEEF domain playing a crucial role in regulating biofilm through c-di-GMP signaling. Conventional antimicrobial strategies often struggle to address infections caused by biofilms due to their poor permeability and specificity. Current methods for disrupting biofilms frequently lack precision and fail to effectively destabilize proteins associated with these structures. Moreover, the potential of DNA aptamers to enhance ubiquitin-mediated proteolysis for regulating biofilm formation remains largely unexplored. This study investigates the use of DNA aptamers as a Molecular glue (MG) to promote ubiquitin-mediated proteolysis and dysregulation of biofilm formation involving the GGEEF domain in Vibrio Cholerae. DNA aptamers targeting the GGEEF domain were synthetically generated based on Hidden Markov Models (HMM), and potential high-affinity candidates were screened. Further, Molecular Docking and Dynamics simulations were conducted to confirm the effects of the DNA aptamers on Protein–Protein Interaction (PPI). The result indicates that among the screened aptamers—Aptamer-6 molecule effectively stabilizes the binding between the GGEEF domain and the ubiquitin ligase. Overall, this research highlights the potential of DNA aptamers as a novel therapeutic tool for destabilizing biofilms in Vibrio cholerae, addressing a significant challenge in combating antibiotic resistance.