Assessment of amino acid charge states based on cryo-electron microscopy and 
molecular dynamics simulations of respiratory complex I

Lasham, Jonathan; Djurabekova, Amina; Kolypetris, Georgios; Zickermann, Volker; Vonck, Janet; Sharma, Vivek

doi:10.1016/j.bbabio.2024.149512

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Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I

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Vonck, Janet
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Lasham, J., Djurabekova, A., Kolypetris, G., Zickermann, V., Vonck, J., & Sharma, V. (2024). Assessment of amino acid charge states based on cryo-electron microscopy and molecular dynamics simulations of respiratory complex I. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1866(1): 149512. doi:10.1016/j.bbabio.2024.149512.

Cite as: https://hdl.handle.net/21.11116/0000-000F-E2B1-9

Abstract

The charge states of titratable amino acid residues play a key role in the function of membrane-bound bioenergetic proteins. However, determination of these charge states both through experimental and computational approaches is extremely challenging. Cryo-EM density maps can provide insights on the charge states of titratable amino acid residues. By performing classical atomistic molecular dynamics simulations on the high resolution cryo-EM structures of respiratory complex I from Yarrowia lipolytica, we analyze the conformational and charge states of a key acidic residue in its ND1 subunit, aspartic acid D203, which is also a mitochondrial disease mutation locus. We suggest that in the native state of respiratory complex I, D203 is negatively charged and maintains a stable hydrogen bond to a conserved arginine residue. Alternatively, upon conformational change in the turnover state of the enzyme, its sidechain attains a charge-neutral status. We discuss the implications of this analysis on the molecular mechanism of respiratory complex I.