Journal
BIOPHYSICAL JOURNAL
Volume 113, Issue 7, Pages 1505-1519Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2017.08.003
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Categories
Funding
- National Science Foundation (NSF) [MCB-1413613, CHE-1346572]
- National Institutes of Health (NIH) [1S10OD018495-01, R01-GM101048, U54-GM087519, P41-GM104601, R01-AI073922, T32 GM007183]
- XSEDE [TG-MCA06N060]
- University of Chicago Materials Research Science and Engineering Center - National Science Foundation (NSF) [DMR-1420709]
- Advanced Photon Source at Argonne National Laboratory under DOE-BES [DE-AC02-06CH11357]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1346572] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1413613] Funding Source: National Science Foundation
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The dynamic nature of lipid membranes presents significant challenges with respect to understanding the molecular basis of protein/membrane interactions. Consequently, there is relatively little known about the structural mechanisms by which membrane-binding proteins might distinguish subtle variations in lipid membrane composition and/or structure. We have previously developed a multidisciplinary approach that combines molecular dynamics simulation with interfacial x-ray scattering experiments to produce an atomistic model for phosphatidylserine recognition by the immune receptor Tim4. However, this approach requires a previously determined protein crystal structure in a membrane-bound conformation. Tim1, a Tim4 homolog with distinct differences in both immunological function and sensitivity to membrane composition, was crystalized in a closed-loop conformation that is unlikely to support membrane binding. Here we have used a previously described highly mobile membrane mimetic membrane in combination with a conventional lipid bilayer model to generate a membrane-bound configuration of Tim1 in silico. This refined structure provided a significantly improved fit of experimental x-ray reflectivity data. Moreover, the coupling of the x-ray reflectivity analysis with both highly mobile membrane mimetic membranes and conventional lipid bilayer molecular dynamics simulations yielded a dynamic model of phosphatidylserine membrane recognition by Tim1 with atomic-level detail. In addition to providing, to our knowledge, new insights into the molecular mechanisms that distinguish the various Tim receptors, these results demonstrate that in silico membrane-binding simulations can remove the requirement that the existing crystal structure be in the membrane-bound conformation for effective x-ray reflectivity analysis. Consequently, this refined methodology has the potential for much broader applicability with respect to defining the atomistic details of membrane-binding proteins.
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