Utilizing a dynamical description of IspH to aid in the development of novel antimicrobial drugs

PLoS Computational Biology
Patrick G BlachlyJ Andrew McCammon

Abstract

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 inaccessible in the absence of HMBPP. In contrast, simulations with HMBPP bound are restricted from accessing the open states sampled by the substrate-free simulations. Further investigation of the substrate-free simulations reveals large fluctuations in the HMBPP binding pocket, as well as allosteric pocket openings - both of which are achieved through the hinge motions of the individual domains in IspH. Coupling these findings with solvent mapping an...Continue Reading

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Citations

Apr 20, 2014·Trends in Pharmacological Sciences·Ruth Nussinov, Chung-Jung Tsai
Aug 27, 2014·The Journal of Cell Biology·Laura CorriganClive Wilson
Nov 18, 2015·Journal of Chemical Theory and Computation·Koichi Tamura, Shigehiko Hayashi
Nov 18, 2014·Journal of Chemical Theory and Computation·Jacob D DurrantRommie E Amaro
Jun 19, 2015·Journal of Molecular Modeling·Zhong Ni, Tian-Cheng Zhang
Oct 29, 2019·The Journal of Physical Chemistry. B·A StelmakhA Baumketner

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Methods Mentioned

BETA
X-ray
electron paramagnetic resonance
PCA

Software Mentioned

Pocket Volume MEasurer ( POVME )
Amsterdam Density Functional
PROpKa
VMD MultiSeq
MK
STRIDE
torsion
AMBER GAFF
cuda engine
MutInf

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