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Molecular mechanism of thiamine pyrophosphate import into mitochondria: a molecular simulation study

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Abstract

The import of thiamine pyrophosphate (TPP) through both mitochondrial membranes was studied using a total of 3-µs molecular dynamics simulations. Regarding the translocation through the mitochondrial outer membrane, our simulations support the conjecture that TPP uses the voltage-dependent anion channel, the major pore of this membrane, for its passage to the intermembrane space, as its transport presents significant analogies with that used by other metabolites previously studied, in particular with ATP. As far as passing through the mitochondrial inner membrane is concerned, our simulations show that the specific carrier of TPP has a single binding site that becomes accessible, through an alternating access mechanism. The preference of this transporter for TPP can be rationalized mainly by three residues located in the binding site that differ from those identified in the ATP/ADP carrier, the most studied member of the mitochondrial carrier family. The simulated transport mechanism of TPP highlights the essential role, at the energetic level, of the contributions coming from the formation and breakage of two networks of salt bridges, one on the side of the matrix and the other on the side of the intermembrane space, as well as the interactions, mainly of an ionic nature, formed by TPP upon its binding. The energy contribution provided by the cytosolic network establishes a lower barrier than that of the matrix network, which can be explained by the lower interaction energy of TPP on the matrix side or possibly a uniport activity.

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Abbreviations

AAC:

ADP/ATP carrier

c-state:

Cytoplasmic-open state

ffTK:

Force field tool kit

IMS:

Intermembrane space

m-state:

Matrix-open state

MIM:

Mitochondrial inner membrane

MOM:

Mitochondrial outer membrane

MCF:

Mitochondrial carrier family

TM:

Transmembrane

TPP:

Thiamine pyrophosphate

TPPT:

Thiamine pyrophosphate transporter

VDAC:

Voltage dependent anion channel

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Acknowledgements

M.P. is a senior research associate and E.M.K. is a postdoctoral researcher of the Fonds de la Recherche Scientifique de Belgique (F.R.S.-F.R.N.S.), Belgium. Computational resources were provided by the Consortium des Équipements de Calcul Intensif (CÉCI) and the F.R.S.-F.N.R.S. under convention 2.5020.11, together with the supercomputing facilities of the Université catholique de Louvain (CISM/UCL), the Université de Liège (ULg) and ULB.

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  1. Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles (ULB), Brussels, Belgium

    F. Van Liefferinge, E.-M. Krammer, J. Waeytens & M. Prévost

  2. Currently at Unité de glycobiologie structurale et fonctionnelle (UGSF), University Lille, CNRS, UMR 8576, Lille, France

    E.-M. Krammer

  3. Institut de Chimie Physique d’Orsay, CNRS UMR8000, Université Paris-Sud, Université Paris-Saclay, Orsay, France

    J. Waeytens

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Van Liefferinge, F., Krammer, EM., Waeytens, J. et al. Molecular mechanism of thiamine pyrophosphate import into mitochondria: a molecular simulation study. J Comput Aided Mol Des 35, 987–1007 (2021). https://doi.org/10.1007/s10822-021-00414-5

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