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Analysis of hydrophobic organization of proteins

  1. Previously, we have developed a new theoretical method to assess in atomic-scale detail hydrophobic properties of globular and membrane proteins (Efremov et al., 1992ab, 1995; Efremov & Alix, 1993; Efremov & Vergoten, 1996). The method is based on the concept of the three-dimensional molecular hydrophobicity potential (MHP). It permits calculation and visualization of MHP in any point of the space, e.g., on the protein surface, in the vicinity of particular residues, in active sites, and so far;
  2. Using the MHP-approach, we have proposed a new algorithm to predict the effect of amino acid replacements on protein stability (Golovanov et al., 1995a–c, 1997, 1998). In the result, detailed atomic-scale characterization of inter-residue contacts (hydrophobic, hydrophilic, unfavorable hydrophobic-to-hydrophilic) and estimation of their relative strength, might be obtained. The method was checked on the mutants of T4 lysozyme, for which thermodynamic data (change in melting temperature and/or change in the free energy of unfolding) and the spatial structures are known. It was shown that the change in the hydrophobic contribution of mutated residue is correlated with the change in stability. The proposed approach can successfully predict the effect of mutations on thermodynamic stability of a protein molecule, which 3D structure is known. The applicability of this method was also checked for the spatial structures of the barnase mutants, obtained by molecular modeling techniques, as well as for misfolded and distorted protein structures (Golovanov et al., 1998);
  3. To characterize in detail the spatial structures of proteins, a new MHP-based algorithm has been developed (Efremov et al., 1995; Golovanov et al., 1995ac). It permits identification of potentially "active" amino acid residues, which are able to take part in intermolecular binding. The spatial structures of barnase and neurotoxin II (NtII) have been characterized, and structural amino acid residues have been identified. Theoretical study of the effects of amino acid replacements, able to increase the stability of these molecules, has been performed;
  4. New software packages, HIPPO and Hi-EXPO, dedicated to rational protein engineering and design of point mutations via analysis of hydrophobicity of inter-residue contacts in proteins and their complexes, have been created (Golovanov et al., 1998). They permit delineation of putative functionally active amino acid residues and residues forming a hydrophobic protein core.

Read about: MHP approach, the “hydrophobicity template” method.

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