Brownian dynamics model of the encounter complex formation of cytochrome c and dimer III respiratory complex in the mitochondrial crista lumenaral space

Abaturova, A.M.; Riznichenko, G.Y.

Авторы: Abaturova A.M., Riznichenko G.Yu
Журнал: Biophysical Reviews
Том: 15
Год издания: 2023
Издательство: Springer Verlag
Местоположение издательства: Germany
Первая страница: 1431
Последняя страница: 1432
Номер статьи: S1.14
DOI: 10.1007/s12551-023-01150-w
Аннотация: Expansion of mitochondrial cristae lumen is observed in many diseases and aging, is accompanied by a decrease in ATP production [1, 2]. These phenomena are associated with disruption of the mitochondrial electron transport chain in the region from III to IV of the respiratory complex, where the electron carrier is the only mobile carrier in the lumen, cytochrome c. A small (about 12 kDa) protein, cytochrome c (cytC), diffuses in the intermembrane and luminal space of mitochondria and carries out electron transfer from the cytochrome c1 subunit of complex III dimer (III2) to complex IV. This reaction can be divided into 2 stages: binding of freely diffusible cytC protein to cytC1 of complex III, and electronic transport between cytochromes. This paper presents a model of the Brownian dynamics of the first stage of this process, i.e., the formation of an encounter complex of the water-soluble cytC protein with the cytC1 cofactor of complex III fixed in the membrane. The model was used to study the influence of the initial position of cytC relative to complex III2 and the role of electrostatic interactions in the formation of the encounter complex.Using the ProKSim program [3], we constructed computer models of diffusion, electrostatic interaction, and binding of oxidized cytC (PDB ID 3O1Y) with reduced cytC1 III2 (PDB ID 1BGY) in solution and in the lumen of the crista. The Poisson-Boltzmann formalism was used to calculate the electrostatic potential around protein molecules. The charges on the protein atoms were arranged in accordance with the CHARMM27 force field, supplemented with parameters for the heme and iron-sulfur cluster. Protein molecules and electrostatic potentials were visualized using PyMol (http://pymol.org/). The estimation of the parameters of the model for the formation of the cytC1-cytC complex was preliminarily performed for the reaction in solution. The values of the model parameters were estimated from the experimental data [4] using the condition that the model and experimental dependences of the binding constant on the ionic strength coincide [5].Respiratory complexes III and IV can form a supercomplex, a respirasome [6], which creates a kind of “electrostatic channel” that directs the movement of oxidized cytC to complex III and the movement of reduced cytC to complex IV, providing fast electron transfer between complexes III and IV. Swelling of cristae in diseases leads to the destruction of respirasomes [7]. Using the model, we studied the influence of the initial positions and orientation of CytC relative to the respiratory complex III on the rate of formation of the CytC1(III2)-CytC complex. The membranes in the model were taken into account as geometric constraints. Dimensions of the reaction volume: crista lumen width (CLW) 12 and 16 nm, membrane length 26 and 30 nm. Kinetic curves for the formation of preliminary complexes were obtained at an electrostatic interaction energy of proteins of -3.7kT and a distance between the Fe atoms of cytC and the cytC1 P subunit III2 of less than 3.5 nm for an ionic strength of 130 mM, pH 7. The kinetic curve of protein binding for each initial position consisted of 20000 points. From the curves, the half-life of the formation of the encounter complex of proteins t1/2 was determined. 60000 numerical experiments were carried out on the diffusion of cytC and the formation of a encounter complex with III2.We studied 7 initial positions of CytC, in which the distance from the Fe atom to the Fe of the heme of the active monomer III was 5.6 nm, 0.5 nm away from the membrane surface. In one series of numerical experiments, the orientation of cytC was random with respect to a fixed position of the center of mass of cytC; in others, it was fixed and corresponded to the average structure of 10000 positions of cytC obtained in preliminary calculations of the diffusion of cytC. CytC acquires such orientations if it has been diffusing for a long time in the electrostatic field of the respirasome before binding with cytC1.For 4 initial positions of cyt C, which are closer to complex IV in the 5GPN respirasome, t1/2 is 0.5–0.9 mks, for the remaining 3 positions t1/2 is 1.2–1.7 mks. With an increase of CLW from 12 to 16 нм, an increase in the probability of finding cytC in the region of the inactive cytC1 D III2 subunit and an increase in the time t1/2 by 4–18% is observed. The greatest difference in t1/2 was obtained for cytC not previously oriented in the field of proteins and from the position closest to IV in the 5GPN respirasome. The resulting effect may contribute to a decrease in the rate of CytC electron transport during the expansion of the cristae and a simultaneous increase in the distance between the respiratory complexes [7], when cytC can’t obtain a preliminary orientation in the resprasome electrostatic field. Further consideration of a detailed model that takes into account the conformation of the formed complexes and the structure of respirasomes in cristae will reveal their effect on electron transfer in the respiratory chain.The study was carried out within the framework of the State Budget Project of Lomonosov Moscow State University No. 121032500060-0.Literature1. L. Colina-Tenorio et al., 2018 Shaping the mitochondrial inner membrane in health and disease, DOI: 10.1111/joim.130312. Siegmund S.E. et al., DOI: 10.1016/j.isci.2018.07.0143. Khruschev S.S. et al., 2013, 47-64., DOI: 10.20537/2076-7633-2013-5-1-47-644. G. Engstrom, R. Rajagukguk, A. J. Saunders, C. N. Patel, S. Rajagukguk, T. Merbitz-Zahradnik, K. Xiao, G. J. Pielak, B. Trumpower, C. A. Yu, L. Yu, B. Durham, F. Millett,Biochemistry, vol.42, pp. 2816-24 (2003), DOI: 10.1021/bi027213g5. Abaturova A.M. et. al. // ITM Web of Conferences, V. 31., 2020. DOI: 10.1051/itmconf/202031040016. Lapuente-Brun, E.; Moreno-Loshuertos, R.; Acin-Perez, R. et al. (2013). Science 340 (6140): 1567–1570. DOI:10.1126/science.12303817. Sara Cogliati et al., 2013 DOI: 10.1016/j.cell.2013.08.032
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Brownian dynamics model of the encounter complex formation of cytochrome c and dimer III respiratory complex in the mitochondrial crista lumenaral spaceстатья

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