Electron transfer and conformational transitions of cytochrome c are modulated by the same dynamical features

Abstract

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Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity

“…This suggests that the MD data we have obtained provides a representative indication of the conformational dynamics of cytochromes c, and therefore is useful for assessing relationships between movement of various regions of cytochrome c and its properties and activities. Interestingly our data do not support the recent conclusion, from much shorter simulations of a range of equine cytochrome c variants, that redox potential is modulated by movement of the 40-57 and 71-85 Ω loops (30). Our data did provide partial support for the previous conclusion that flexibility of the 71-85 Ω may regulate the alkaline transition pK (30).…”

“…Interestingly our data do not support the recent conclusion, from much shorter simulations of a range of equine cytochrome c variants, that redox potential is modulated by movement of the 40-57 and 71-85 Ω loops (30). Our data did provide partial support for the previous conclusion that flexibility of the 71-85 Ω may regulate the alkaline transition pK (30). The differences between our repeated, independent 200 ns simulations for each variant emphasizes that one should take care when making conclusions from short MD simulations of cytochrome c. Even our comparatively long simulations, although supporting conclusions from other methods, show significant stochastic variation.…”

“…Residues with highest Cα RMSF (apart from the extreme N-and C-termini) are within the 19-36 and 40-57 Ω loops, with 8/24 and 16/24 simulations respectively having residues with Cα RMSF > 1 Å ( Figure S6). This is consistent with previous MD and hydrogen-deuterium exchange data (7,28,30,(34)(35)(36). There was no correlation between RMSF in the 19-36 and 40-57 Ω loops (r = 0.28, P = 0.18 with two-tailed Pearson correlation), suggesting these loops move independently.…”

“…Our simulations also provide an opportunity to test conclusions made from other MD data regarding the role of conformational dynamics in influencing the redox potential and the alkaline transition pK. Recently Oviedo-Rouco et al reported 50 ns simulations of equine ferric cytochrome c and selected variants (30). They concluded that a decrease in redox potential correlated with an increase in RMSF for the entire protein, the 70-85 Ω loop, and to a lesser extent the 40-57 Ω loop.…”

“…There have been numerous MD studies on cytochromes c from a range of species, originally focusing on protein folding and unfolding, and more recently on the impact of post-translational modifications and mutations (29)(30)(31). Here we analyzed four independent simulations of 200 ns for WT and each variant, using human G41S cytochrome c (3NWV) as the starting structure.…”