Molecular Simulation On Interaction Mechanism Of Molecular Chaperone HdeA

HdeA is an acid stress chaperone which is located in the pathogenic enteric bacterial periplasm space. When the pathogenic enteric bacteria enter into the extremely acidic conditions of the stomach, HdeA rapidly transitions from an inactive folded dimer to a chaperone-active unfolded monomer which binds to substrate proteins and prevent their aggregation, eventually the pathogenic enteric bacteria can reach the gut safely and cause severe diseases. At present, there are many unsolved questions in HdeA, including the details of conformational changes of HdeA at different pH values and the interaction mechanism between HdeA and substrate proteins. In order to explore these questions, the molecular simulation technology was performed in the research.The constant pH molecular dynamics technology was used to explore the conformational changes of HdeA dimer at different pH values. Analysing the effect of protonation of acidic residues on the stability of the HdeA dimer interface, D20, D43 and D51 were found having the largest destabilizing effect on the dimer interface. Compared with the secondary structure of HdeA at different pH values, it was found that the protonation of acidic residues may result in the partial unfolding and disorder of HdeA structure. However, it was not the sole trigger for HdeA dissociation.Molecular docking and molecular dynamics simulation were performed on the research of interaction mechanism between HdeA and the substrate proteins DegP and SurA for the first time. MM-PBSA method was used to calculate the binding free energy. Our results showed that the binding affinities of HdeA-DegP and HdeA-SurA were-47.34kcal/mol and-102.92kcal/mol respectively, and the hydrophobic interaction was the main driving force for the binding of HdeA with substrate proteins. The results of complex model, H-bond and energy decompositions indicated that the hydrophobic region of HdeA was the main area for the binding of HdeA to DegP and SurA, the non-hydrophobic region of HdeA was the main area for the formation of hydrogen bond, L22, A23, D25, E26, L39, N40, Q64, K84 and the amino acid residues located in the C-terminal and N-terminal played an important role in the binding of HdeA to DegP and SurA. We believe that the findings revealed in this work not only provide a better understanding of the interaction mechanism between HdeA and its substrate proteins, but also may be of general value to guide the design of HdeA inhibitors in pharmaceutical industries.