Refinement of protein structures in explicit solvent

Authors

  • Jens P. Linge,

    1. Unité de Bio-Informatique Structurale, Institut Pasteur, Paris, France
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  • Mark A. Williams,

    1. Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom
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  • Christian A.E.M. Spronk,

    1. Centre for Molecular and Biomolecular Informatics, University of Nijmegen, Nijmegen, The Netherlands
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  • Alexandre M. J. J. Bonvin,

    Corresponding author
    1. Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands
    • Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands, or Michael Nilges, Unité de Bio-Informative Structurale, Institut Pasteur, 25–28 rue du Dr Roux, 75015 Paris, France
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  • Michael Nilges

    Corresponding author
    1. Unité de Bio-Informatique Structurale, Institut Pasteur, Paris, France
    • Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands, or Michael Nilges, Unité de Bio-Informative Structurale, Institut Pasteur, 25–28 rue du Dr Roux, 75015 Paris, France
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Abstract

We present a CPU efficient protocol for refinement of protein structures in a thin layer of explicit solvent and energy parameters with completely revised dihedral angle terms. Our approach is suitable for protein structures determined by theoretical (e.g., homology modeling or threading) or experimental methods (e.g., NMR). In contrast to other recently proposed refinement protocols, we put a strong emphasis on consistency with widely accepted covalent parameters and computational efficiency. We illustrate the method for NMR structure calculations of three proteins: interleukin-4, ubiquitin, and crambin. We show a comparison of their structure ensembles before and after refinement in water with and without a force field energy term for the dihedral angles; crambin was also refined in DMSO. Our results demonstrate the significant improvement of structure quality by a short refinement in a thin layer of solvent. Further, they show that a dihedral angle energy term in the force field is beneficial for structure calculation and refinement. We discuss the optimal weight for the energy constant for the backbone angle omega and include an extensive discussion of meaning and relevance of the calculated validation criteria, in particular root mean square Z scores for covalent parameters such as bond lengths. Proteins 2003;50:496–506. © 2003 Wiley-Liss, Inc.

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