Computational insights into iron coordination disruption in the human transferrin–neisseria meningitidis bacterial protein complex

Dervişoğlu Özdemir, CelileDuran, Gizem NurFındık, VolkanÖzbil, MehmetSağ Erdem, Safiye2026-01-162026-01-162025Dervişoğlu Özdemir, C., Duran, G. N., Fındık, V., Özbil, M., & Sağ Erdem, S. (2025). Computational insights into iron coordination disruption in the human transferrin–neisseria meningitidis bacterial protein complex. Inorganics, 13(12), pp. 1-27. https://doi.org/10.3390/inorganics131203842304-6740https://doi.org/10.3390/inorganics13120384https://hdl.handle.net/20.500.13055/1250Among many metal ions in biological systems, iron plays a fundamental role. Transferrins are iron-binding glycoproteins responsible for transporting Fe3+ in vertebrate blood. Neisse ria 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 trans fer 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.eninfo:eu-repo/semantics/openAccessNeisseria MeningitidisTransferrinTransferrin Binding ProteinsMolecular Dynamics SimulationsM06 FunctionalDensity Functional TheoryONIOMComputational insights into iron coordination disruption in the human transferrin–neisseria meningitidis bacterial protein complexArticle10.3390/inorganics131203841312127Q2WOS:001646716800001Q2