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[摘要]：We investigate the connection between sequence evolution of the human immunodeficiency virus (HIV) type 1 protease under neutral selection or selective pressure induced by protease inhibitors and the functional and molecular-stability characteristics of the molecule in the physical domain. To this end we analyze sequence data on more than 45,000 patients with bioinformatical tools, namely mutual information between residue pairings. In addition we perform extensive computations on the molecular mechanics of the molecule subject to artificial mutations. The changes in the mechanics and dynamics of the molecule in three-dimensional space upon perturbation are then related to the sequence stability as described by the mutual information. We distinguish physical interactions by their evolutionary background and give hints for potential new drug targets. In addition we discuss how such targets can be efficiently chosen to give the HI virus less opportunity to develop resistance towards such drugs while maintaining the protease function at the same time. The interactions between residue no. 28 and 23 ' in different chains as well as the interaction between residue no. 92 and 94 within one chain were identified as particular crucial. In addition we find interactions in the beta-sheet-dimerization interface to be important for conserving the protein function and stability while these are at the same time evolutionary conserved - implications of and comparisons to experimental results are finally discussed. (c) 2008 Elsevier B.V. All rights reserved. |
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