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Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3177-82. Epub 2007 Feb 20.

Near-native structure refinement using in vacuo energy minimization.

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Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305-5126, USA.


One of the greatest shortcomings of macromolecular energy minimization and molecular dynamics techniques is that they generally do not preserve the native structure of proteins as observed by x-ray crystallography. This deformation of the native structure means that these methods are not generally used to refine structures produced by homology-modeling techniques. Here, we use a database of 75 proteins to test the ability of a variety of popular molecular mechanics force fields to maintain the native structure. Minimization from the native structure is a weak test of potential energy functions: It is complemented by a much stronger test in which the same methods are compared for their ability to attract a near-native decoy protein structure toward the native structure. We use a powerfully convergent energy-minimization method and show that, of the traditional molecular mechanics potentials tested, only one showed a modest net improvement over a large data set of structurally diverse proteins. A smooth, differentiable knowledge-based pairwise atomic potential performs better on this test than traditional potential functions. This work is expected to have important implications for protein structure refinement, homology modeling, and structure prediction.

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