Abstract
Proteins need to be unfolded when translocated through the pores in mitochondrial and other cellular membranes. Knotted proteins, however, might get stuck during this process, jamming the pore, since the diameter of the pore is smaller than the size of maximally tightened knot. The jamming probability dramatically increases as the magnitude of the driving force exceeds a critical value, Fc. In this numerical study, we show that for deep knots Fc lies below the force range over which molecular import motors operate, which suggest that in these cases the knots will tighten and block the pores. Next, we show how such topological traps might be prevented by using a pulling protocol of a repetitive, on-off character. Such a repetitive pulling is biologically relevant, since the mitochondrial import motor, like other molecular motors transforms chemical energy into directed motions via nucleotide-hydrolysis-mediated conformational changes, which are cyclic in character.
Highlights
Through Brownian dynamics simulations of knotted protein translocation we show that knot tightening probability strongly depends on the force with which the protein is pulled into the pore
Brownian dynamics simulations of protein translocation suggest that the pore jamming by tight protein knots can be avoided by the use of a pulling protocol of a repetitive, on-off character
This mechanism is remarkably simple and yet very robust - all of the proteins considered here, no matter how large and complex, will eventually make it through the pore, becoming untied in the process. Such a repetitive pulling is biologically relevant, since the mitochondrial import motors are cyclic in character
Summary
Proteins need to be unfolded when translocated through the pores in mitochondrial and other cellular membranes. Through Brownian dynamics simulations of knotted protein translocation we show that knot tightening probability strongly depends on the force with which the protein is pulled into the pore. For deep knots (with more than 30 aminoacids between the end of the knotted core and the free end of the protein) Fc is shown to lie below the force range over which molecular import motors operate, which suggest that in these cases knots will tighten and block the pores. On the other hand the comparison of the protein folding times in the model and in vivo leads to τ ~ μs (e.g. ubiqutin in silico folds on the timescale of 103 τ27 whereas in vivo - it is in tens of millisecond range[28]). The comparison of the forces measured in AFM experiments with those recorded in the numerical simulations for 28 different proteins have shown a good correlation (with Pearson correlation coefficient of 0.89) provided that the force unit in the model, ε/Å, is translated into about 70pN24,30
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