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Molecular Design of Specific Metal‐Binding Peptide Sequences from Protein Fragments: Theory and Experiment
Author(s) -
Kožíšek Milan,
Svatoš Aleš,
Buděšínský Miloš,
Muck Alexander,
Bauer Mikael C.,
Kotrba Pavel,
Ruml Tomáš,
Havlas Zdeněk,
Linse Sara,
Rulíšek Lubomír
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200800178
Subject(s) - peptide , metal , amino acid , chemistry , metal ions in aqueous solution , side chain , crystallography , peptide sequence , ion , stereochemistry , polymer , organic chemistry , biochemistry , gene
A novel strategy is presented for designing peptides with specific metal‐ion chelation sites, based on linking computationally predicted ion‐specific combinations of amino acid side chains coordinated at the vertices of the desired coordination polyhedron into a single polypeptide chain. With this aim, a series of computer programs have been written that 1) creates a structural combinatorial library containing Z i –(X) n –Z j sequences ( n =0–14; Z: amino acid that binds the metal through the side chain; X: any amino acid) from the existing protein structures in the non‐redundant Protein Data Bank; 2) merges these fragments into a single Z 1 –(X) n 1–Z 2 –(X) n 2–Z 3 –(X) n 3–⋅⋅⋅–Z j polypeptide chain; and 3) automatically performs two simple molecular mechanics calculations that make it possible to estimate the internal strain in the newly designed peptide. The application of this procedure for the most M 2+ ‐specific combinations of amino acid side chains (M: metal; see L. Rulíšek, Z. Havlas J. Phys. Chem. B 2003 , 107 , 2376–2385) yielded several peptide sequences (with lengths of 6–20 amino acids) with the potential for specific binding with six metal ions (Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ , Cd 2+ and Hg 2+ ). The gas‐phase association constants of the studied metal ions with these de novo designed peptides were experimentally determined by MALDI mass spectrometry by using 3,4,5‐trihydroxyacetophenone as a matrix, whereas the thermodynamic parameters of the metal‐ion coordination in the condensed phase were measured by isothermal titration calorimetry (ITC), chelatometry and NMR spectroscopy methods. The data indicate that some of the computationally predicted peptides are potential M 2+ ‐specific metal‐ion chelators.