biostudies-literatureBlachly PGHoward Hughes Medical InstituteNIGMS NIH HHSPHS HHSe1003395https://www.ebi.ac.uk/biostudies/studies/S-EPMC3868525biostudies-literatureUnknown9(12)The nonmevalonate pathway is responsible for isoprenoid production in microbes, including H. pylori, M. tuberculosis and P. falciparum, but is nonexistent in humans, thus providing a desirable route for antibacterial and antimalarial drug discovery. We coordinate a structural study of IspH, a [4Fe-4S] protein responsible for converting HMBPP to IPP and DMAPP in the ultimate step in the nonmevalonate pathway. By performing accelerated molecular dynamics simulations on both substrate-free and HMBPP-bound [Fe4S4](2+) IspH, we elucidate how substrate binding alters the dynamics of the protein. Using principal component analysis, we note that while substrate-free IspH samples various open and closed conformations, the closed conformation observed experimentally for HMBPP-bound IspH is inaccessiPLoS computational biologyUtilizing a dynamical description of IspH to aid in the development of novel antimicrobial drugs.PMC3868525NIHGM31749T32 GM008326Blachly PGMcCammon JAWilliams SLde Oliveira CAfalseUtilizing a dynamical description of IspH to aid in the development of novel antimicrobial drugs.The nonmevalonate pathway is responsible for isoprenoid production in microbes, including H. pylori, M. tuberculosis and P. falciparum, but is nonexistent in humans, thus providing a desirable route for antibacterial and antimalarial drug discovery. We coordinate a structural study of IspH, a [4Fe-4S] protein responsible for converting HMBPP to IPP and DMAPP in the ultimate step in the nonmevalonate pathway. By performing accelerated molecular dynamics simulations on both substrate-free and HMBPP-bound [Fe4S4](2+) IspH, we elucidate how substrate binding alters the dynamics of the protein. Using principal component analysis, we note that while substrate-free IspH samples various open and closed conformations, the closed conformation observed experimentally for HMBPP-bound IspH is inaccessi2013-01-01T00:00:00Z20132026-04-14T17:16:03.174Z2019-03-27T01:18:45ZS-EPMC38685252436724810.1371/journal.pcbi.1003395