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Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer

Amita R. Sahoo, Paulo C. T. Souza, Zhiyuan Meng, Matthias Buck
doi: https://doi.org/10.1101/2021.09.10.459840
Amita R. Sahoo
1Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, U. S. A.
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Paulo C. T. Souza
2Molecular Microbiology and Structural Biochemistry (MMSB, UMR 5086), CNRS & University of Lyon, 7 Passage du Vercors, 69007, Lyon, France
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Zhiyuan Meng
1Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, U. S. A.
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Matthias Buck
1Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, U. S. A.
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  • For correspondence: matthias.buck@case.edu
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Summary

Determination of the structure and dynamics of transmembrane (TM) regions of single-transmembrane receptors is key to understanding their mechanism of signal transduction across the plasma membrane. Although many studies have been performed on isolated soluble extra- and intracellular receptor domains in aqueous solutions, limited knowledge exists on the lipid embedded TM domain. In this study, we examine the assembly of configurations of receptor TM region dimers using the Martini 3 force field for coarse-grain (CG) molecular dynamics simulations. This recently published version of Martini has new bead types and sizes, which allows more accurate predictions of molecular interactions compared to the previous versions. At first glance our results with Martini 3 simulations show only a reasonable agreement with ab initio predictions using PREDDIMER (for TM domains only), AlphaFold2 Multimer and with available NMR derived structures for TM helix dimers. Specifically, 6 of 11 CG TM structures are similar to the NMR structures (within < 3.5 Å mainchain RMSD) compared to 10 of 11 and 9 of 11 using PREDDIMER and Alphafold, respectively (7 structures of the latter are within 1.5 Å) Surprisingly, AlphaFold2 predictions are more comparable with NMR structures when the database of 2001 (mainly composed of soluble proteins) instead of 2020 PDB structures are used. While there are some differences in the conditions used, the CG simulations primarily reveal that alternate configurations of the TM dimers that are sampled, which readily interconvert with a predominant population. The implications of these findings for our understanding of the signalling mechanism of TM receptors are discussed, including opportunities for the development of new pharmaceuticals, some of which are peptide based.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Added new Fig S2 and table S5. Modified the text.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 07, 2023.
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Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer
Amita R. Sahoo, Paulo C. T. Souza, Zhiyuan Meng, Matthias Buck
bioRxiv 2021.09.10.459840; doi: https://doi.org/10.1101/2021.09.10.459840
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Transmembrane region dimer structures of Type 1 receptors readily sample alternate configurations: MD simulations using the Martini 3 coarse grained model compared to AlphaFold2 Multimer
Amita R. Sahoo, Paulo C. T. Souza, Zhiyuan Meng, Matthias Buck
bioRxiv 2021.09.10.459840; doi: https://doi.org/10.1101/2021.09.10.459840

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