The Impact of Amino Acid Side Chain Mutations in Conformational Design of Peptides and Proteins

Authors

  • Burkhardt Laufer Dr.,

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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    • These authors contributed equally to this work

  • Andreas O. Frank Dr.,

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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    • These authors contributed equally to this work

  • Jayanta Chatterjee Dr.,

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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  • Thomas Neubauer Dipl.-Chem.,

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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  • Carles Mas-Moruno Dr.,

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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  • Grit Kummerlöwe M. Sc.,

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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  • Horst Kessler Prof. Dr.

    1. Institute for Advanced Study at the Department Chemie and Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany), Fax: (+49)89-289-13210
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Abstract

Local energetic effects of amino acid replacements are often considered to have only a moderate influence on the backbone conformation of proteins or peptides. As these effects are difficult to determine experimentally, no comparison has yet been performed. However, knowledge of the influence of side chain mutations is essential in protein homology modeling and in optimizing biologically active peptide ligands in medicinal chemistry. Furthermore, the tool of N-methylation of peptides is of increasing importance for the design of peptidic drugs to gain oral availability or receptor selectivity. However, N-methylation is often accompanied by considerable population of cis-peptide bond structures, resulting in completely different conformations compared with the parent peptide. To retain a favored structure, it might be important to understand the effect of different side chains on the backbone conformation and to enable the introduction of an N-methylation at the right position without disturbing a biologically active conformation. In order to detect even small energetic effects due to side chain mutations, we employed a trick to investigate the structural equilibrium of a selected cyclic pentapeptide in which two conformations are equally populated. Very small energetic differences between both conformations could easily be determined experimentally by identifying shifts in the population of both isomers.

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