Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies

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 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). It is found that the conformational change of the ligand dihydropteroate sulfathiazole 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, some important hydrogen bonds of the mutation systems are disrupted during the simulations. But the shortening of the distance between residue Thr67 and the ligand would cause significant change of the binding pose in the K220Q system. These studies of DHPS family will be helpful for further drug resistance investigations. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:24.