Molecular basis of protein-DNA interactions between Halalkalibacterium halodurans MntR and its DNA operator sequence

Transition metals such as iron, zinc and manganese are essential for bacterial survival. A pivotal role in regulation of manganese homeostasis in bacterium Halalkalibacterium halodurans has MntR protein (HhMntR). In this work, molecular dynamics simulations of holoprotein (with Mn²⁺) and apoprotein (without Mn²⁺) HhMntR in complex with DNA mntA operator were conducted and enabled understanding of interaction between HhMntR and DNA on molecular level. Molecular mechanism through which affinity of HhMntR towards DNA is increased upon Mn²⁺ binding was revealed. Holoprotein binds DNA through stable and consistent noncovalent interactions, while apoprotein shows highly dynamic behavior, attaching to and detaching from the DNA backbone and inner grooves on a nanosecond time scale. The same observations are seen even during the simulations that started with protein and DNA separated from the complex. Additionally, key amino acids involved in the formation of the HhMntR-DNA complex were identified, leading to the proposal of a molecular framework that allows HhMntR to perform its biological function as a transcription factor. Overall, observed behaviors promote the lateral movement of HhMntR along the DNA sequence, enabling the protein to remain close to the DNA while it seeks out specific base pairs for strong binding upon activation by Mn²⁺.