Biophysical Society Thematic Meeting | Trieste 2024

Emerging Theoretical Approaches to Complement Single-Particle Cryo-EM

Thursday Speaker Abstracts

MOLECULAR INSIGHTS INTO MITOCHONDRIAL ENERGY PRODUCTION BY INTEGRATING CRYO ELECTRON MICROSCOPY AND BIOCHEMISTRY WITH COMPUTER SIMULATIONS Vivek Sharma ; 1 University of Helsinki, Department of Physics, Helsinki, Finland In several organisms [1], enzyme-catalyzed translocation of ions across the membrane drives the generation of ATP. The membrane-bound respiratory complexes of the mitochondrial electron transport chain catalyze redox-driven proton pumping, but the molecular mechanisms have remained unknown. The respiratory complexes coalesce together to form higher order assemblies called the mitochondrial supercomplexes [1], but the functional basis of these also remain debated. Here, results from recent multiscale computer simulations on isolated mitochondrial complexes and supercomplexes will be presented, which helps in delineating the molecular basis of energy production in mitochondria and bacteria. Coarse-grained and atomistic molecular dynamics (MD) simulations on high-resolution cryo-EM structures of mitochondrial supercomplexes [2] provide insights on the coupled dynamics of proteins and membrane and their interactions. Respiratory complex I and Mrp-type antiporter structures are studied with long time-scale atomistic MD simulations and hybrid QM/MM free energy calculations [2-4] to decipher the energetics of quinone redox chemistry and protonation dynamics. We discuss an approach of combining pKa prediction with cryo-EM density map analysis that can help in improved atomic modeling of the density data [5] and deeper understanding of molecular mechanisms of bioenergetic enzymes [6]. [1] M. Wikström, C. Pecorilla, V. Sharma, The Enzymes, 54 (2023) 15-36.[2] Y.-Ch. Shin, P. Latorre-Muro, A. Djurabekova, O. Zdorevskyi, Ch. F. Bennett, N. Burger, K. Song, Ch. Xu, V. Sharma, M. Liao, P. Puigserver. bioRxiv (2024)[3] Y. Lee, O. Haapanen, A. Altmeyer, et al., Nature Communications, 13 (2022) 6091.[4] O. Zdorevskyi, A. Djurabekova, J. Lasham, V. Sharma, Chemical Science 14 (2023) 6309 6318.[5] J. Lasham, A. Djurabekova, V. Zickermann, J. Vonck, V. Sharma, The Journal of Physical Chemistry B 128 (2024) 2304-2316.[6] A. Djurabekova, J. Lasham, O. Zdorevskyi, V. Zickermann, V. Sharma, Biochemical Journal, 481 (2024) 499–514.

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