Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Feb 3;64(6):e202417804.
doi: 10.1002/anie.202417804. Epub 2025 Jan 13.

Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions

Affiliations

Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions

Fabian Schuhmann et al. Angew Chem Int Ed Engl. .

Abstract

Cross-linking mass spectrometry (XL-MS) enables the mapping of protein-protein interactions on the cellular level. When applied to all compartments of mitochondria, the sheer number of cross-links and connections can be overwhelming, rendering simple cluster analyses convoluted and uninformative. To address this limitation, we integrate the XL-MS data, 3D electron microscopy data, and localization annotations with a supra coarse-grained molecular dynamics simulation to sort all data, making clusters more accessible and interpretable. In the context of mitochondria, this method, through a total of 6.9 milliseconds of simulations, successfully identifies known, suggests unknown protein clusters, and reveals the distribution of inner mitochondrial membrane proteins allowing a more precise localization within compartments. Our integrative approach suggests, that two so-far ambigiously placed proteins FAM162A and TMEM126A are localized in the cristae, which is validated through super resolution microscopy. Together, this demonstrates the strong potential of the presented approach.

Keywords: 3D volumetric imaging; cross-linking mass spectrometry; mitochondrial protein distribution; molecular dynamics; supra coarse-grained.

PubMed Disclaimer

References

    1. I. M. Nooren, J. M. Thornton, EMBO J. 2003, 22, 3486.
    1. K. Luck, D. K. Kim, L. Lambourne, K. Spirohn, B. E. Begg, W. Bian, R. Brignall, T. Cafarelli, F. J. Campos-Laborie, B. Charloteaux, D. Choi, A. G. Coté, M. Daley, S. Deimling, A. Desbuleux, A. Dricot, M. Gebbia, M. F. Hardy, N. Kishore, J. J. Knapp, I. A. Kovács, I. Lemmens, M. W. Mee, J. C. Mellor, C. Pollis, C. Pons, A. D. Richardson, S. Schlabach, B. Teeking, A. Yadav, M. Babor, D. Balcha, O. Basha, C. Bowman-Colin, S. F. Chin, S. G. Choi, C. Colabella, G. Coppin, C. D'Amata, D. De Ridder, S. De Rouck, M. Duran-Frigola, H. Ennajdaoui, F. Goebels, L. Goehring, A. Gopal, G. Haddad, E. Hatchi, M. Helmy, Y. Jacob, Y. Kassa, S. Landini, R. Li, N. van Lieshout, A. MacWilliams, D. Markey, J. N. Paulson, S. Rangarajan, J. Rasla, A. Rayhan, T. Rolland, A. San-Miguel, Y. Shen, D. Sheykhkarimli, G. M. Sheynkman, E. Simonovsky, M. Taşan, A. Tejeda, V. Tropepe, J. C. Twizere, Y. Wang, R. J. Weatheritt, J. Weile, Y. Xia, X. Yang, E. Yeger-Lotem, Q. Zhong, P. Aloy, G. D. Bader, J. De Las Rivas, S. Gaudet, T. Hao, J. Rak, J. Tavernier, D. E. Hill, M. Vidal, F. P. Roth, M. A. Calderwood, Nature 2020, 580, 402.
    1. T. Rolland, M. Taşan, B. Charloteaux, S. J. Pevzner, Q. Zhong, N. Sahni, S. Yi, I. Lemmens, C. Fontanillo, R. Mosca, A. Kamburov, S. D. Ghiassian, X. Yang, L. Ghamsari, D. Balcha, B. E. Begg, P. Braun, M. Brehme, M. P. Broly, A. R. Carvunis, D. Convery-Zupan, R. Corominas, J. Coulombe-Huntington, E. Dann, M. Dreze, A. Dricot, C. Fan, E. Franzosa, F. Gebreab, B. J. Gutierrez, M. F. Hardy, M. Jin, S. Kang, R. Kiros, G. N. Lin, K. Luck, A. Macwilliams, J. Menche, R. R. Murray, A. Palagi, M. M. Poulin, X. Rambout, J. Rasla, P. Reichert, V. Romero, E. Ruyssinck, J. M. Sahalie, A. Scholz, A. A. Shah, A. Sharma, Y. Shen, K. Spirohn, S. Tam, A. O. Tejeda, S. A. Wanamaker, J. C. Twizere, K. Vega, J. Walsh, M. E. Cusick, Y. Xia, A. L. Barabási, L. M. Iakoucheva, P. Aloy, J. De Las Rivas, J. Tavernier, M. A. Calderwood, D. E. Hill, T. Hao, F. P. Roth, M. Vidal, Cell 2014, 159, 1212.
    1. E. L. Huttlin, R. J. Bruckner, J. A. Paulo, J. R. Cannon, L. Ting, K. Baltier, G. Colby, F. Gebreab, M. P. Gygi, H. Parzen, J. Szpyt, S. Tam, G. Zarraga, L. Pontano-Vaites, S. Swarup, A. E. White, D. K. Schweppe, R. Rad, B. K. Erickson, R. A. Obar, K. G. Guruharsha, K. Li, S. Artavanis-Tsakonas, S. P. Gygi, J. Wade Harper, Architecture of the human interactome defines protein communities and disease networks 2017.
    1. T. C. Branon, J. A. Bosch, A. D. Sanchez, N. D. Udeshi, T. Svinkina, S. A. Carr, J. L. Feldman, N. Perrimon, A. Y. Ting, Nat. Biotechnol. 2018, 36, 880.

MeSH terms

Substances

LinkOut - more resources