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

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.