Unveiling structural dynamics and allosteric vulnerabilities in Klebsiella pneumoniae KPHS_11890 : an integrated DRKG-MD study

Abstract

Klebsiella pneumoniae (K. pneumoniae), a multidrug-resistant Gram-negative bacillus, represents a significant global health threat due to its role in hospital-acquired infections and the emergence of carbapenem-resistant hypervirulent strains. This study integrates the Drug Repurposing Knowledge Graph (DRKG) with molecular dynamics (MD) simulations to identify and validate stable structural segments of the KPHS_11890 gene, which encodes a membrane fusion protein of the AcrAB-TolC efflux pump that is critical for antibiotic resistance in K. pneumoniae. Using the PyKEEN framework, a knowledge graph embedding model was trained on a comprehensive dataset combining DrugBank, K. pneumoniae strain sequences, and NCBI databases, identifying KPHS_11890 as a top-ranked candidate (Hits@10 = 0.1602). The structural reliability of the target was first confirmed via rigorous quality assessment (Ramachandran plot, ERRAT, and ProSA), followed by triplicate 100-ns molecular dynamics simulations using GROMACS 2025. The integrated analysis of essential dynamics and free energy landscapes (FEL) revealed a thermodynamically stable core domain (residues 18–342) and a critical functional hinge region near residue 115. The structural rigidity of the core suggests minimized entropic penalties for inhibitor binding, while the identified hinge motion presents a specific mechanical vulnerability for allosteric locking. This integrated DRKG-MD approach not only efficiently pinpoints high-potential targets but also elucidates their biophysical mechanisms, providing a robust structural basis for designing novel inhibitors to overcome efflux pump-mediated resistance.