Abstract
We present a scheme, based on existing and newly developed computational tools, for the determination of the overall conformation of biological macromolecules composed by domains or subunits, using from such structural determination easily available solution properties. In a multi-scale approach, atomic-level structures are used to provide simple shapes for the subunits, which are put together in a coarse grained model, with a few parameters that determine the overall shape of the macromolecule. Computer programs, like those in the HYDRO suite that evaluate the properties of either atomic or coarse-grained models. In this paper we present a new scheme for a global fit of multiple properties, implemented in a new computer program, HYDROFIT, which interfaces with the programs of the HYDRO suite to find an optimum, best-fitting structure in a robust but simple way. The determination of the overall structure of the native antibody IgG3, bearing a long hinge, and that of the hingeless mutant m15 is presented to test and confirm the validity of this simple, systematic and efficient scheme.
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Bernado P, García de la Torre J, Pons M (2002) Interpretation of 15N NMR relaxation data of globular proteins using hydrodynamic calculations with HYDRONMR. J Biomol NMR 23:139–150. doi:10.1023/A:1016359412284
Bloomfield VA, Dalton WO, Holde KEV (1967) Frictional coefficients of multisubunit structures I. Theory. Biopolymers 5:135–148. doi:10.1002/bip.1967.360050202
Brady RL, Edwards DJ, Hubbard RE, Jiang JS, Lange G, Roberts SM, Todd RJ, Adair JR, Emtage JS, King DJ, Low DC (1992) Crystal structure of a chimeric Fab′ fragment of an antibody binding tumour cells. J Mol Biol 227:253–264. doi:10.1016/0022-2836(92)90695-G
Burton D (1987) Structure and function of antibodies, In: molecular genetics of immunoglobulin. Elsevier, New York
Byron O (2000) Hydrodynamic bead modelling of biological macromolecules. Methods Enzymol 321:278–304. doi:10.1016/S0076-6879(00)21199-3
Byron O (2008) Hydrodynamic modelling: the solution conformation of macromolecules and their complexes, In: Correia J, Detrich H (eds) “methods in cell biology, vol 84, biophysical tools for biologists, vol 1 in vitro techniques, of analytical ultracentrifuge data in biophysical techniques, pp 327–373
Carrasco B, García de la Torre J (1999) Hydrodynamic properties of rigid particles. Comparison of different modelling and computational procedures. Biophys J 76:3044–3057
Carrasco B, García de la Torre J, Byron O, King D, Walters C, Jones S, Harding SE (1999) Novel size-independent modeling of the dilute solution conformation of the immunoglobulin IgG Fab′ domain using SOLPRO and ELLIPS. Biophys J 77:2902–2910
Carrasco B, García de la Torre J, Davis KG, Jones S, Athwal D, Walters C, Burton DR, Harding SE (2001) Crystallohydrodynamics for solving the hydration problem for multi-domain proteins: open physiological conformations of human IgG. Biophys Chem 93:181–196. doi:10.1016/S0301-4622(01)00220-4
Deisenhofer J (1981) Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9 A and 2.8 A resolution. Biochemistry 20:2361–2370. doi:10.1021/bi00512a001
Fernandes MX, Bernado P, Pons M, García de la Torre J (2001) An analytical solution to the problem of the orientation of rigid particles by planar obstacles. J Am Chem Soc 123:12037–12047. doi:10.1021/ja011361x
Fernandes MX, Ortega A, Martínez MCL, García de la Torre J (2002) Calculation of hydrodynamic properties of small nucleic acids from their atomic structures. Nucleic Acids Res 30:1782–1788. doi:10.1093/nar/30.8.1782
Furtado PB, Whitty PW, Robertson A, Eaton JT, Almogren A, Kerr MA, Wolf HM, Perkins SJ (2004) Solution structure determination of monomeric human IgA2 by X-ray and neutron scattering, analytical ultracentrifugation and constrained modelling: a comparison with monomeric human IgA1. J Mol Biol 338:921–941. doi:10.1016/j.jmb.2004.03.007
García de la Torre J, Carrasco B (2002) Hydrodynamic properties of rigid macromolecules composed of ellipsoidal and cylindrical subunits. Biopolymers 63:163–167. doi:10.1002/bip.10013
García de la Torre J, Navarro S, Martínez MCL, Diaz FG, Lopez Cascales JJ (1994) HYDRO: a computer program for the prediction of hydrodynamic properties of macromolecules. Biophys J 67:530–531
García de la Torre J, Carrasco B, Harding SE (1997) SOLPRO: theory and computer program for the prediction of SOLution PROperties of rigid macromolecules and bioparticles. Eur Biophys J 25:361–372. doi:10.1007/s002490050049
García de la Torre J, Huertas ML, Carrasco B (2000) Calculation of hydrodynamic properties of globular proteins from their atomic-level structures. Biophys J 78:719–730
García de la Torre J, Llorca O, Carrascosa JL, Valpuesta JM (2001) HYDROMIC: prediction of hydrodynamic properties of rigid macromolecular structures obtained from electron microscopy. Eur Biophys J 30:457–462. doi:10.1007/s002490100176
García de la Torre J, Pérez Sánchez HE, Ortega A, Hernández Cifre JG, Fernandes MX, Baños FGD, Martínez MCL (2003) Calculation of the solution properties of flexible macromolecules: methods and applications. Eur Biophys J 32:477–486. doi:10.1007/s00249-003-0292-0
García de la Torre J, Bernado P, Pons M (2005) Hydrodynamic models and computational methods for NMR relaxation. Methods Enzymol 394:419–430. doi:10.1016/S0076-6879(05)94017-2
Gregory L, Davis KS, Sheth B, Boyd J, Jefferis R, Naves C, Burton D (1987) The solution conformation of the subclass of human IgG deduced from sedimentation and small-angle X-ray scattering. Mol Immunol 24:821–829. doi:10.1016/0161-5890(87)90184-2
Harding SE (1995) On the hydrodynamic analysis of macromolecular conformation. Biophys Chem 55:69–93. doi:10.1016/0301-4622(94)00143-8
Harding SE, Longman E, Carrasco B, Ortega A, García de la Torre J (2003) Studying antibody conformations by ultracentrifugation and hydrodynamic modeling methods in molecular biology, vol 248. Humana Press, Totowa, pp 93–113
Harris LJ, Larson SB, Skaletsky E, McPherson A (1998a) Comparison of the conformations of two intact antibodies with hinges. Immunol Rev 163:35–43. doi:10.1111/j.1600-065X.1998.tb01186.x
Harris LJ, Skaletsky E, McPherson A (1998b) Crystallographic structure of an intact IgG1 monoclonal antibody. J Mol Biol 275:861–872. doi:10.1006/jmbi.1997.1508
Harvey SH, García de la Torre J (1980) Coordinate systems for modelling the hydrodynamic resistance and diffusion coefficients of irregularly shaped rigid macromolecules. Macromolecules 13:960–964. doi:10.1021/ma60076a037
Longman E, Kreusel K, Tendler SB, Fiebig I, King K, Adiar J, O’Shea P, Ortega A, García de la Torre J (2003) Estimating domain orientation of two human antibody IgG4 chimeras by crystallohydrodynamics. Eur Biophys J 32:502–510. doi:10.1007/s00249-003-0314-y
Lu Y, Harding S, Michaelsen T, Longman E, Davis KG, Ortega A, Grossman G, Sandlie I, García de la Torre J (2007) Solution conformation of wild type and mutant IgG3 and IgG4 immunoglobulins using crystallohydrodynamics: possible implications for complement activation. Biophys J 93:3733–3744. doi:10.1529/biophysj.107.108993
Nöllmann M, Stark WM, Byron O (2005) A global multi-technique approach to study low-resolution solution structures. J Appl Cryst 38:874–887. doi:10.1107/S0021889805026191
Ortega A, García de la Torre J (2003) Hydrodynamic properties of rodlike and disklike particles in dilute solution. J Chem Phys 119:9914–9919. doi:10.1063/1.1615967
Ortega A, García de la Torre J (2005) Efficient, accurate calculation of rotational diffusion and NMR relaxation of globular proteins from atomic-level structures and approximate hydrodynamic calculations. J Am Chem Soc 127:12764–12765. doi:10.1021/ja053080l
Ortega A, García de la Torre J (2007) Equivalent radii and ratios of radii from solution properties as indicators of macromolecular shape, conformation and flexibility. Biomacromolecules 8:2464–2475. doi:10.1021/bm700473f
Perkins SJ, Bonner A (2008) Structure determinations of human and chimeric antibodies by solution scattering and constrained molecular modelling. Biochem Soc Trans 36:37–42. doi:10.1042/BST0360037
Tanford C (1961) Physical chemistry of macromolecules. Wiley, New York
Yamakawa H (1971) Modern theory of polymer solutions. Harper & Row, New York
Zipper P, Durchschlag H (2003) Modeling of protein solution structures. J Appl Cryst 36:509–514. doi:10.1107/S0021889803001870
Acknowledgments
This work was supported by grant CTQ-2006-06831 from Ministerio de Ciencia e Innovación (MICINN), including FEDER funds, and Fundación Séneca-CARM, grant no. 04531/GERM/06. A. O. and D. A. acknowledge fellowships from MICINN.
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Amorós, D., Ortega, A., Harding, S.E. et al. Multi-scale calculation and global-fit analysis of hydrodynamic properties of biological macromolecules: determination of the overall conformation of antibody IgG molecules. Eur Biophys J 39, 361–370 (2010). https://doi.org/10.1007/s00249-008-0388-7
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DOI: https://doi.org/10.1007/s00249-008-0388-7