Decoding Structural Properties of a Partially Unfolded Protein Substrate: En Route to Chaperone Binding

• DOI: 10.1371/journal.pcbi.1004496
• Publication Date: 2015-09-22T18:08:58Z
• Authors: Suhani Nagpal; Satyam Tiwari; Koyeli Mapa; Lipi Thukral
• Keywords: Chaperone (clinical)

Many proteins comprising of complex topologies require molecular chaperones to achieve their unique three-dimensional folded structure. The E.coli chaperone, GroEL binds with a large number unfolded and partially proteins, facilitate proper folding prevent misfolding aggregation. Although the major structural components are well defined, scaffolds non-native substrates that determine chaperone-mediated have been difficult recognize. Here we performed all-atomistic replica-exchange dynamics simulations dissect ensemble an obligate folder, DapA. Thermodynamics analyses unfolding revealed populated intermediates distinct characteristics. We found surface exposed hydrophobic patches significantly increased, primarily contributed from native β-sheet elements. validate properties these conformers using experimental data, including circular dichroism (CD), 1-anilinonaphthalene-8-sulfonic acid (ANS) binding measurements previously reported hydrogen-deutrium exchange coupled mass spectrometry (HDX-MS). Further, constructed network graphs elucidate long-range intra-protein connectivity intermediate topologies, demonstrating regions serve as central "hubs". Overall, our results implicate genomic variations (or mutations) in protein structures might disrupt topological signatures disabling folding, leading formation aggregates.