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Dihydropteroate synthase (DHPS) is essential for the folic acid biosynthetic pathway in prokaryotes, the mutation forms for DHPS are found to be relative to the urgent drug resistance problems.In addition, the DHPS acts as an attractive target for the antimicrobial drugs, but the detailed reaction mechanism of it is still unknown.In our study, the Bacillus anthracis DHPS (BaDHPS) was selected for molecular dynamics and binding free energy studies to investigate the biochemistry behaviors of the wild-type and mutation form BaDHPS proteins (D184N and K220Q), and Yersinia pestis DHPS (YpDHPS) was chosen for the investigation of protein-ligand interactions and condensation reaction mechanism by using classical molecular dynamic and quantum mechanics/molecular mechanics metadynamic simulation methods.It is found that the conformational change of the ligand DHP-STZ binding site in mutation D184N and K220Q systems is mainly attributed from the Loop 1, Loop 2 and Loop 7 regions, and the binding free energy of these mutation systems is lower than that of the wild-type system.Additionally, the QM/MM calculations show that the estimated reaction barrier of the SN1 mechanism is lower than that of the SN2 mechanism, which means that it is much easier for this reaction to proceed through the SN1 mechanism.These studies of DHPS family will be helpful for the further drug resistance investigations.