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      Evolutionary Pareto-optimization of stably folding peptides

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      1 ,   2 , 3 ,
      BMC Bioinformatics
      BioMed Central

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          Abstract

          Background

          As a rule, peptides are more flexible and unstructured than proteins with their substantial stabilizing hydrophobic cores. Nevertheless, a few stably folding peptides have been discovered. This raises the question whether there may be more such peptides that are unknown as yet. These molecules could be helpful in basic research and medicine.

          Results

          As a method to explore the space of conformationally stable peptides, we have developed an evolutionary algorithm that allows optimization of sequences with respect to several criteria simultaneously, for instance stability, accessibility of arbitrary parts of the peptide, etc. In a proof-of-concept experiment we have perturbed the sequence of the peptide Villin Headpiece, known to be stable in vitro. Starting from the perturbed sequence we applied our algorithm to optimize peptide stability and accessibility of a loop. Unexpectedly, two clusters of sequences were generated in this way that, according to our criteria, should form structures with higher stability than the wild-type. The structures in one of the clusters possess a fold that markedly differs from the native fold of Villin Headpiece. One of the mutants predicted to be stable was selected for synthesis, its molecular 3D-structure was characterized by nuclear magnetic resonance spectroscopy, and its stability was measured by circular dichroism. Predicted structure and stability were in good agreement with experiment. Eight other sequences and structures, including five with a non-native fold are provided as bona fide predictions.

          Conclusion

          The results suggest that much more conformationally stable peptides may exist than are known so far, and that small fold classes could comprise well-separated sub-folds.

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          Most cited references32

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          A solution for the best rotation to relate two sets of vectors

          W Kabsch (1976)
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            MOLMOL: a program for display and analysis of macromolecular structures.

            MOLMOL is a molecular graphics program for display, analysis, and manipulation of three-dimensional structures of biological macromolecules, with special emphasis on nuclear magnetic resonance (NMR) solution structures of proteins and nucleic acids. MOLMOL has a graphical user interface with menus, dialog boxes, and on-line help. The display possibilities include conventional presentation, as well as novel schematic drawings, with the option of combining different presentations in one view of a molecule. Covalent molecular structures can be modified by addition or removal of individual atoms and bonds, and three-dimensional structures can be manipulated by interactive rotation about individual bonds. Special efforts were made to allow for appropriate display and analysis of the sets of typically 20-40 conformers that are conventionally used to represent the result of an NMR structure determination, using functions for superimposing sets of conformers, calculation of root mean square distance (RMSD) values, identification of hydrogen bonds, checking and displaying violations of NMR constraints, and identification and listing of short distances between pairs of hydrogen atoms.
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              Protein backbone angle restraints from searching a database for chemical shift and sequence homology.

              Chemical shifts of backbone atoms in proteins are exquisitely sensitive to local conformation, and homologous proteins show quite similar patterns of secondary chemical shifts. The inverse of this relation is used to search a database for triplets of adjacent residues with secondary chemical shifts and sequence similarity which provide the best match to the query triplet of interest. The database contains 13C alpha, 13C beta, 13C', 1H alpha and 15N chemical shifts for 20 proteins for which a high resolution X-ray structure is available. The computer program TALOS was developed to search this database for strings of residues with chemical shift and residue type homology. The relative importance of the weighting factors attached to the secondary chemical shifts of the five types of resonances relative to that of sequence similarity was optimized empirically. TALOS yields the 10 triplets which have the closest similarity in secondary chemical shift and amino acid sequence to those of the query sequence. If the central residues in these 10 triplets exhibit similar phi and psi backbone angles, their averages can reliably be used as angular restraints for the protein whose structure is being studied. Tests carried out for proteins of known structure indicate that the root-mean-square difference (rmsd) between the output of TALOS and the X-ray derived backbone angles is about 15 degrees. Approximately 3% of the predictions made by TALOS are found to be in error.
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                Author and article information

                Journal
                BMC Bioinformatics
                BMC Bioinformatics
                BioMed Central
                1471-2105
                2008
                19 February 2008
                : 9
                : 109
                Affiliations
                [1 ]Institute for Functional Genomics, University of Regensburg, Josef-Engert-Strasse 9, 93053 Regensburg, Germany
                [2 ]Computer Engineering and Networks Laboratory, ETH Zurich, Gloriastrasse 35, Zürich, Switzerland
                [3 ]Centre for Medical Biotechnology, University of Duisburg-Essen, Universitätsstrasse, 45117 Essen, Germany
                Article
                1471-2105-9-109
                10.1186/1471-2105-9-109
                2263021
                18284690
                4be49b89-8dd1-43f4-8e46-2ae0b745fc50
                Copyright © 2008 Gronwald et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 October 2007
                : 19 February 2008
                Categories
                Research Article

                Bioinformatics & Computational biology
                Bioinformatics & Computational biology

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