High-resolution protein complexes from integrating genomic information with molecular simulation

Alexander Schug, Martin Weigt, José N. Onuchic, Terence Hwa, Hendrik Szurmant
2009 Proceedings of the National Academy of Sciences of the United States of America  
Bacteria use two-component signal transduction systems (TCS) extensively to sense and react to external stimuli. In these, a membrane-bound sensor histidine kinase (SK) autophosphorylates in response to an environmental stimulus and transfers the phosphoryl group to a transcription factor/response regulator (RR) that mediates the cellular response. The complex between these two proteins is ruled by transient interactions, which provides a challenge to experimental structure determination
more » ... ues. The functional and structural homolog of an SK/RR pair Spo0B/Spo0F, however, has been structurally resolved. Here, we describe a method capable of generating structural models of such transient protein complexes. By using existing structures of the individual proteins, our method combines bioinformatically derived contact residue information with molecular dynamics simulations. We find crystal resolution accuracy with existing crystallographic data when reconstituting the known system Spo0B/Spo0F. Using this approach, we introduce a complex structure of TM0853/TM0468 as an exemplary SK/RR TCS, consistent with all experimentally available data. direct coupling analysis ͉ signal transduction ͉ structure based simulations ͉ transient protein complexes ͉ two component system *Note that Spo0B along with SK proteins are structurally distinct from Hpt-type phosphotransferases, commonly utilized as intermediary proteins in phosphorelays. This article contains supporting information online at www.pnas.org/cgi/content/full/ 0912100106/DCSupplemental.
doi:10.1073/pnas.0912100106 pmid:20018738 pmcid:PMC2799721 fatcat:xysrdmrrcbcp5fxaul4wfludsm