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In previous literature, it was found that the activity of New Delhi Metallo-β-lactamase-1 (NDM-1) was inhibited by 2,6-dipicolinic acid (DPA) derivatives. To identify the mechanism of interaction between the inhibitors and NDM-1, molecular dynamics simulations were performed for the complex systems. Via the molecular modelling, inhibitors were found to be able bind to the region of catalytic activity of NDM-1. However, the detailed binding sites of the inhibitors differed with their structures. It was determined that His189, Lys211, Met248, Ser249, His250, and Ser251 are key residues for the binding of inhibitor 36 with NDM-1, and Asp124 is the only critical residue in the NDM-1-DPA complex. Furthermore, because of the interaction of the benzene ring in inhibitor 36 with the side chain of Lys211, inhibitor 36 can form 4 strong hydrogen bonds with protein. For the NDM-1-DPA complex, owing to the absence of the aniline group, DPA can only form a weak interaction with the residues around the binding site of NDM-1, except for Asp124, leading to a weaker inhibitory activity. Therefore, we believe that the strong interaction of the inhibitor with Lys211 results in effective inhibition, and the aniline group is the element required for the inhibitory activity. [ABSTRACT FROM AUTHOR]

ATP-binding cassette (ABC) transporters are integral membrane proteins that utilised energy from ATP hydrolysis to translocate substrates across the membrane. In addition to the common nucleotide-binding domains (NBDs) and transmembrane domains (TMDs), the methionine ABC transporter has C-terminal regulatory domains (C2 domains) that belong to ACT protein family. When the amount of methionine in the cell is high, the transport stops. This phenomenon is called trans-inhibition. To understand how a trans-inhibited protein returns to an uninhibited, resting state, we performed steered molecular dynamic simulations with and without the substrates. From the simulations, we observed some important conformational changes in the whole ABC transporter, including the constriction in the translocation pathway in the TMDs and approach of the NBDs. However, the C2 domains behaved differently in two types of the simulations. These findings might help to explain the relationship of the conformational changes of the C2 domains with the rearrangements of the NBDs or TMDs, and provide a way to understand the trans-inhibition from an opposite direction. [ABSTRACT FROM AUTHOR]

To achieve the structural basis to produce a more accurate model of the catalytic active site of Stx2, we carried out molecular docking and molecular dynamics simulations of adenosine–Stx2 complex, and used the molecular mechanics/Poisson–Boltzmann surface area method to determine the associated free energy profiles. The results reveal that the electrostatic interactions play an important role in the stabilisation of the binding site of Stx2–adenosine, and the key residues of Ser113, Arg119, Arg125 and Arg170 in Stx2–adenosine complex are identified based on the residue decomposition analysis. With this approach, we are able to demonstrate that the substrate adenosine is located in the cavity formed by A-subunit, which is similar to the available experimental binding pattern of Stx2–adenine except for adenine being more close to the residues of Arg170, Tyr77 and Val78. The conformational difference that lies in adenosine is stabilised by the residues around the binding site of adenosine–Stx2, which leads to that the adenine base and furan ring of adenosine are dragged by the residues in the opposite direction during the catalytic process. The above results indicate that the residues around the binding site of adenosine in Stx2 should be used as catalytic active site to depurinate a specific adenine base from 28S rRNA. [ABSTRACT FROM PUBLISHER]