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Computational Insights into Iron Coordination Disruption in the Human Transferrin–Neisseria meningitidis Bacterial Protein Complex

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Vydáno v:Inorganics vol. 13, no. 12 (2025), p. 384-411
Hlavní autor: Dervişoğlu Özdemir Celile
Další autoři: Duran, Gizem Nur, Fındık Volkan, Özbil Mehmet, Sağ Erdem Safiye
Vydáno:
MDPI AG
Témata:
Physiology
Crystal structure
Iron
Glycoproteins
Protons
Ferric ions
Meningitis
Computer applications
Electrostatic properties
Transferrins
Coordination
Drug development
Transferrin
Drug resistance
Proteins
Simulation
Signal transduction
Quantum physics
Disruption
Ligands
Metal ions
Molecular dynamics
Enzymes
Vertebrates
Neisseria meningitidis
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Abstrakt:Among many metal ions in biological systems, iron plays a fundamental role. Transferrins are iron-binding glycoproteins responsible for transporting Fe3+ in vertebrate blood. Neisseria meningitidis, a Gram-negative pathogen causing meningitis, relies on iron for survival and acquires it from human transferrin (hTf) using two surface proteins, TbpA and TbpB. These proteins interact with hTf to form a ternary TbpA–TbpB–hTf complex, enabling iron capture from the host. The absence of an experimental crystal structure for this complex has hindered computational studies, a detailed understanding of Fe3+ dissociation, and designing efficient therapeutics. This study presents the first computational model of the ternary complex, its validation, and molecular dynamics simulations. Structural analyses revealed key electrostatic interactions regulating Fe3+ coordination and essential contact regions between proteins. The role of Lys359 from TbpA was investigated via QM/MM calculations by evaluating Fe3+ binding energies of isolated hTf, the ternary complex, and Lys359Ala, Lys359Arg, Lys359Asp mutant models. Results revealed that the proton transfer from Lys359 leads to disruption of Tyr517–Fe3+ coordination, facilitating iron transfer to the bacterial system. Natural bond orbital analysis confirmed this mechanism. The findings provide new molecular insight into N. meningitidis iron acquisition and identify Lys359 as a potential target for covalent inhibitor design, guiding the development of novel therapeutics against meningococcal infection.
ISSN:2304-6740
DOI:10.3390/inorganics13120384
Zdroj:Materials Science Database