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Computational studies on imidazole heme conformations

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Abstract

Density functional theory computations of heme with ionized propionic acid groups, axially coordinated with two imidazoles, were performed for different mutual orientations of the imidazole planes. Environmental influences from water or protein were considered with a continuum dielectric medium by solving the Poisson equation. In vacuum, optimized geometries yielded imidazole–heme conformations where the NH groups of imidazoles are oriented toward the heme propionic groups in agreement with data from crystal structures of heme proteins. Conformational free-energy dependencies of the mutual orientation of axially ligated imidazoles calculated in protein (ε=10) and water (ε=80) environments confirmed the vacuum results, albeit the energy difference between the preferred and the 180° opposite orientations of the imidazole ligand decreased from 3.84 kcal/mol in vacuum to 2.35 and 2.40 kcal/mol in protein and water, respectively. Two main factors determine the imidazole orientation: (1) the direct intramolecular electrostatic interactions of propionic groups with the polar NH groups of imidazole and (2) the electrostatic interaction of the total dipole moment of the imidazole–heme complex with the reaction field. In vacuum, only the first type of interaction is present, while in a dielectric medium the latter effect becomes competitive at high dielectric constant, resulting in a decrease of the orientational preference. Interestingly, the orientational preference of the imidazole axially ligated to heme becomes even more pronounced, if the negatively charged propionates are neutralized by counter charges that mimic salt bridges or protonation of the propionates.

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Abbreviations

DFT:

Density functional theory

ESP:

Electrostatic potential

PDB:

Protein Data Bank

RESP:

Restraint electrostatic potential

vdW:

van der Waals

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Acknowledgements

We thank Donald Bashford and Martin Karplus for providing the programs MEAD and CHARMM, respectively. S.D.Z. is grateful for generous support by the Humboldt foundation. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 498 Project A5; Forschergruppe 475; GRK 80/2; GRK 268; GRK 788/1).

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Authors and Affiliations

  1. Institute of Chemistry, Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, Takustrasse 6, 14195, Berlin, Germany

    Artur S. Galstyan & Ernst-Walter Knapp

  2. Department of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box, 11001, Belgrade, Yugoslavia

    Snežana D. Zarić

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  1. Artur S. Galstyan
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  2. Snežana D. Zarić
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  3. Ernst-Walter Knapp
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Correspondence to Ernst-Walter Knapp.

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Galstyan, A.S., Zarić, S.D. & Knapp, EW. Computational studies on imidazole heme conformations. J Biol Inorg Chem 10, 343–354 (2005). https://doi.org/10.1007/s00775-005-0642-8

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