Gregory T. Tietjen, Javier L. Baylon, Daniel Kerr, Zhiliang Gong, J. Michael
Henderson, Charles T. R. Heffern, Mati Meron, Binhua Lin, Mark L. Schlossman,
Erin J. Adams, Emad Tajkhorshid, and Ka Yee C. Lee.
Coupling X-ray reflectivity and in silico binding to yield dynamics
of membrane recognition by Tim1.
Biophysical Journal, 113:1505-1519, 2017.
(PMC: PMC5627149)
TIET2017-ET
The dynamic nature of lipid membranes presents significant challenges
with respect to understanding the molec-
ular 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 scat-
tering 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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