Crystallohydrodynamics for solving the hydration problem for multi-domain proteins: open physiological conformations for human IgG.

نویسندگان

  • B Carrasco
  • J Garcia de la Torre
  • K G Davis
  • S Jones
  • D Athwal
  • C Walters
  • D R Burton
  • S E Harding
چکیده

Hydrodynamic methods provide a route for studying the low-resolution conformation--in terms of time-averaged spatial orientation of the Fab' and Fc domains relative to each other--of the human IgG subclasses, IgG1, IgG2, IgG3 and IgG4 in the environment in which many exist naturally---a solution. Representative modelling strategies are now available using 'shell-bead' or 'shell' modelling of the surface of the molecules with the size-independent programme SOLPRO [J. Garcia de la Torre, S.E. Harding, B. Carrasco, Eur. Biophys. J. 28 (1999) 119-132]. The shell model fits to the equivalent inertial surface ellipsoids of the published crystal structures for the Fab' and Fc domains of IgG are made and an apparent hydration delta(app) of 0.51g/g for Fab' and 0.70 g/g for the glycoprotein Fc are obtained, which yield an average value of (0.59+/-0.07) g/g for the intact antibody (2 Fab'+1 Fc). The relative orientations of these domains for each of the IgG subclasses is then found (using where appropriate a cylindrical hinge) from SOLPRO by modelling the Perrin function, P (i.e. 'frictional ratio due to shape') using this delta(app) and experimentally measured sedimentation coefficients. All the IgG subclasses appear as open, rather than compact structures with the degree of openness IgG3>IgG1>(IgG2, IgG4), with IgG3 and IgG1 non-coplanar. The hingeless mutant IgGMcg, with s degrees (20,w) approximately 6.8 S yields a coplanar structure rather similar to IgG2 and IgG4 and consistent with its crystallographic structure. The extension of this procedure for representing solution conformations of other antibody classes and other multi-domain proteins is indicated.

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عنوان ژورنال:
  • Biophysical chemistry

دوره 93 2-3  شماره 

صفحات  -

تاریخ انتشار 2001