Abstract
We present an original approach based on full-atom normal mode analysis (NMA) aimed to expand the general framework of homology modeling. Using the rat heme-free oxygenase 1 as a case system, we show how NMA can be used to model different physiologically relevant conformations of the same protein. Starting from a unique heme-bound X-ray structure, and using two structural templates corresponding to a human and an incomplete rat heme-free structures, we generate models of the rat unbound species with open and closed conformations. Less than 100 lowest frequency modes of the target were sufficient to obtain the heme-free conformations, the closest to the templates. The rat HO-1 model built for the open form shows features similar to the open form of the human heme-free oxygenase, and the one built for the closed form was similar to the incompletely resolved X-ray structure of the same protein available in the Protein DataBank. In the latter case, the use of NMA was particularly useful since it allowed to build a complete structure and therefore to discuss on the reason of the structural differences between open and closed forms. This study shows that the amount of main chain flexibility provided by the normal modes can lead to major improvements in homology modeling approaches. Such applications will allow the characterization of alternative conformations of a target protein with respect to the templates and/or the construction of good quality 3D models based on existing templates with unresolved parts in their tertiary structure.
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Regional Biophysics Conference of the National Biophysical Societies of Austria, Croatia, Hungary, Italy, Serbia, and Slovenia.
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Maréchal, JD., Perahia, D. Use of normal modes for structural modeling of proteins: the case study of rat heme oxygenase 1. Eur Biophys J 37, 1157–1165 (2008). https://doi.org/10.1007/s00249-008-0279-y
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DOI: https://doi.org/10.1007/s00249-008-0279-y