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Updated: Apr 30, 2026
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Fosfomycin induced structural change in fosfomycin resistance kinases FomA: molecular dynamics and molecular docking
Yun-Jian Wu1, Qing-Chuan Zheng, Ji-Long Zhang
1State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, 130023, Jilin, P R China.
Abstract:
Fosfomycin resistance kinases FomA, one of the key enzymes responsible for bacterial resistances to fosfomycin, has gained much attention recently due to the raising public concern for multi-drug resistant bacteria. Using molecular docking followed by molecular dynamics simulations, our group illustrated the process of fosfomycin induced conformational change of FomA. The detailed roles of the catalytic residues (Lys18, His58 and Thr210) during the formation of the enzyme-substrate complex were shown in our research. The organization functions of Gly53, Gly54, Ile61 and Leu75 were also highlighted. Furthermore, the cation-π interaction between Arg62 and Trp207 was observed and speculated to play an auxiliary role in the conformation change process of the enzyme. This detailed molecular level illustration of the formation of FomA·ATP·Mg·Fosfomycin complex could provide insight for both anti-biotic discovery and improvement of fosfomycin in the future.
Insights
Fosfomycin resistance enzyme FomA
Area of Science:
- Biochemistry and Molecular Biology
- Antimicrobial Resistance Research
- Structural Biology
Background:
- Fosfomycin resistance is a growing global health concern, driven by multi-drug resistant bacteria.
- The enzyme FomA is crucial for bacterial resistance to the antibiotic fosfomycin.
- Understanding FomA's mechanism is vital for developing new antimicrobial strategies.
Purpose of the Study:
- To elucidate the molecular mechanism of fosfomycin-induced conformational changes in FomA.
- To detail the roles of key catalytic and organizational residues in enzyme-substrate complex formation.
- To investigate potential auxiliary interactions aiding the conformational change.
Main Methods:
- Utilized molecular docking to predict binding interactions.
- Employed molecular dynamics simulations to analyze enzyme conformational changes.
- Focused on the FomA·ATP·Mg·Fosfomycin complex formation.
Main Results:
- Illustrated the step-by-step conformational change of FomA upon fosfomycin binding.
- Identified specific roles for catalytic residues (Lys18, His58, Thr210) and organizational residues (Gly53, Gly54, Ile61, Leu75).
- Observed a cation-π interaction between Arg62 and Trp207, potentially assisting conformational change.
Conclusions:
- Provided a detailed molecular-level understanding of FomA-fosfomycin complex formation.
- The findings offer insights for novel antibiotic discovery targeting FomA.
- This research can guide the improvement of existing fosfomycin-based therapies.
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