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Influence of \( {\text{NH - }}{{\text{S}}^\gamma } \) bonding interactions on the structure and dynamics of metallothioneins

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Abstract

Mammalian metallothioneins (\( {\text{M}}_7^{\text{IIMTs}} \)) show a clustered arrangement of the metal ions and a nonregular protein structure. The solution structures of Cd3-thiolate cluster containing β-domain of mouse β-MT-1 and rat β-MT-2 show high structural similarities, but widely differing structure dynamics. Molecular dynamics simulations revealed a substantially increased number of \( {\text{NH - }}{{\text{S}}^\gamma } \) hydrogen bonds in β-MT-2, features likely responsible for the increased stability of the Cd3-thiolate cluster and the enfolding protein domain. Alterations in the \( {\text{NH - }}{{\text{S}}^\gamma } \) hydrogen-bonding network may provide a rationale for the differences in dynamic properties encountered in the β-domains of MT-1, -2, and -3 isoforms, believed to be essential for their different biological function.

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Abbreviations

MT:

Metallothionein

β-MT:

β-domain of metallothionein

MD:

Molecular dynamics

RMSD:

Root-mean-square deviation

aa:

Amino acid

H-bond:

Hydrogen bond

NOE:

Nuclear Overhauser effect

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Acknowledgments

This work was supported by the Swiss National Science Foundation Grant 3100A0-111884 (to M.V), the Spanish Ministerio de Educación y Ciencia (PROFIT PSE0100000-2007-1) and Spanish Ministerio de Ciencia e Innovación (BIO2008-0205) (to B.O), and Fundación Ramón Areces, Spain, postdoctoral fellowship (to N.R.I).

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland

    Núria Romero-Isart & Milan Vašák

  2. Structural Bioinformatics Lab. (GRIB) Barcelona Research Park of Biomedicine (PRBB), Universitat Pompeu Fabra-IMIM, 08003, Barcelona, Catalonia, Spain

    Baldo Oliva

Authors
  1. Núria Romero-Isart
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  2. Baldo Oliva
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  3. Milan Vašák
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Corresponding authors

Correspondence to Baldo Oliva or Milan Vašák.

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Fig. S1

Experimental structures and averaged structures after the simulations of β-MT-1 and β-MT-2 are shown. \( {{\text{C}}^\alpha } \) trace of the averaged conformations (in white) of Cd3β-MT-1 (a) and Cd3β-MT-2 (b) obtained from the last 4 ns of MD simulation superimposed with their respective experimental NMR structures (cyan). Metal-thiolate clusters resulting from the superimpositions are shown as balls and sticks. (DOC 6212 kb)

Fig. S2

Time series of the electrostatic energy components of (a) Cd3β-MT-1 and (b) Cd3β-MT-2 during the 5 ns MD simulations. Energetic components are grouped according to the chemical origin of the interaction: protein refers to atoms of the amino acid residues and cadmium refers to Cd2+ atoms. Continuous line: protein-protein and protein-cadmium interactions; line plus circles: cadmium-cadmium interactions. (DOC 3747 kb)

Fig. S3

Time series (ps) of RMS deviations (Å) of the backbone (black) and all (red) atoms of the S6P,S8P+T5 mutant of Cd3β-MT-1. All combinations of isomeric states of prolyl residues are considered: a) trans-trans; b) trans-cis; c) cis-trans; and d) cis-cis. (DOC 3343 kb)

Fig. S4

\( {{\text{C}}_\alpha } \) atom-positional RMS fluctuations (Å) per residue around the averaged structures in the last 4ns of the S6P,S8P+T5 mutant of Cd3β-MT-1. All combinations of isomeric states of prolyl residues are considered: a) trans-trans; b) trans-cis; c) cis-trans; and d) cis-cis. (DOC 1180 kb)

Table S1

Hydrogen bonds present in the S6P,S8P+T5 mutant of Cd3β-MT-1 with percentages larger than 50% of hydrogen bond formation between donor and acceptor atoms along the equilibrium time of the simulation (4 ns). All combinations of isomeric states of prolyl residues are considered: trans-trans, trans-cis, cis-trans and cis-cis. \( {\text{NH - }}{{\text{S}}^\gamma } \) H-bonds are highlighted in bold. (DOC 42 kb)

Table S2

Metal-thiolate cluster topology of Cd3Cys9 in the S6P,S8P+T5 mutant of Cd3β-MT-1. All combinations of isomeric states of prolyl residues are considered: transtrans, trans-cis, cis-trans and cis-cis. Time-averaged and fluctuations (SD) of bond lengths and bond angles between bridging (Sb) or terminal (St) sulfur atoms and cadmium ions (Cd). The calculated virtual entropy shows the local disorder of the cluster atoms Cd3S9. (DOC 39 kb)

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Romero-Isart, N., Oliva, B. & Vašák, M. Influence of \( {\text{NH - }}{{\text{S}}^\gamma } \) bonding interactions on the structure and dynamics of metallothioneins. J Mol Model 16, 387–394 (2010). https://doi.org/10.1007/s00894-009-0542-x

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