Journal
BIOLOGICAL CHEMISTRY
Volume 394, Issue 11, Pages 1529-1541Publisher
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2013-0188
Keywords
entropy; eubacterium; free energy; linezolid; MM-PBSA; molecular dynamics simulations
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Funding
- International NRW Research School BioStruct
- Ministry of Innovation, Science and Research of the State North Rhine-Westphalia
- Heinrich-Heine-University of Dusseldorf
- Entrepreneur Foundation at the Heinrich-Heine-University of Dusseldorf
- Julich Supercomputing Center (NIC project) [5921]
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Oxazolidinone antibiotics bind to the highly conserved peptidyl transferase center in the ribosome. For developing selective antibiotics, a profound understanding of the selectivity determinants is required. We have performed for the first time technically challenging molecular dynamics simulations in combination with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations of the oxazolidinones linezolid and radezolid bound to the large ribosomal subunits of the eubacterium Deinococcus radiodurans and the archaeon Haloarcula marismortui. A remarkably good agreement of the computed relative binding free energy with selectivity data available from experiment for linezolid is found. On an atomic level, the analyses reveal an intricate interplay of structural, energetic, and dynamic determinants of the species selectivity of oxazolidinone antibiotics: A structural decomposition of free energy components identifies influences that originate from first and second shell nucleotides of the binding sites and lead to (opposing) contributions from interaction energies, solvation, and entropic factors. These findings add another layer of complexity to the current knowledge on structure-activity relationships of oxazolidinones binding to the ribosome and suggest that selectivity analyses solely based on structural information and qualitative arguments on interactions may not reach far enough. The computational analyses presented here should be of sufficient accuracy to fill this gap.
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