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Abstract

We suppose that folding of proteins occurs cotranslationally by the following scheme. The polypeptide chains enter the folding sites from protein translocation complexes (ribosome, translocation machinery incorporated in membranes) directionally with the N-terminus and gradually. The chain starts to fold as soon as its N-terminal residue enters the folding site from the translocation complex. The folding process accompanies the translocation of the chain to its folding site and is completed after the C-terminal residue leaves the translocation complex. Proteins fold in sequential stages, by translocation of their polypeptide into folding compartments. At each stage a particular conformation of the N-terminal part of the chain that has emerged from the translocation complex is formed. The formation of both the particular conformations of the N-terminal chain segment at each folding stage and the final native protein conformation at the last stage occurs in a time that does not exceed the duration of the fastest elongation cycle on the ribosome.

Molecular Simulations of Cotranslational Protein Folding: Fragment Stabilities, Folding Cooperativity, and Trapping in the Ribosome

“…In an attempt to determine an appropriate rate for “synthesizing” residues in the simulations, the experimental translation rate was first compared to the experimental refolding rates of CI2 and barnase. Although in vivo rates of translation can vary considerably [ 64 , 65 ], they can average around 20 residues per second [ 93 ], which is similar to the experimentally measured refolding rates of both CI2 and barnase in water (50s −1 [ 39 ] and 13s −1 [ 42 ], respectively). The same proteins refold in the simulations with median folding times of approximately 280 ns and approximately 395 ns, respectively (see Results ) which indicates that new amino acids should be introduced in the simulations at intervals of perhaps a few hundred nanoseconds; because of computational considerations, a value of 100 ns was chosen, which, as noted above, corresponds to 4 million simulation steps.…”

Molecular simulations of cotranslational protein folding: fragment stabilities, folding cooperativity and trapping in the ribosome tunnel

“…Although in vivo rates of translation can vary considerably [64,65], they can average around 20 residues per second [93], which is similar to the experimentally measured refolding rates of both CI2 and barnase in water (50s −1 [39] and 13s −1 [42], respectively). The same proteins refold in the simulations with median folding times of approximately 280 ns and approximately 395 ns, respectively (see Results) which indicates that new amino acids should be introduced in the simulations at intervals of perhaps a few hundred nanoseconds; because of computational considerations, a value of 100 ns was chosen, which, as noted above, corresponds to 4 million simulation steps.…”

Sequential search leads to faster, more efficient fragment-basedde novoprotein structure prediction

“…This is consistent with the notion that protein folding is a series of small optimization problems where segments of the chain fold independently (foldons) and then collapse to the complete structure ( Hu et al , 2013 ; Maity et al , 2005 ). Given the amount of experimental evidence to support the notion that proteins are folding as they are being translated ( Basharov, 2000 ; Fedorov and Baldwin, 1997 ; Giglione et al , 2009 ; Holtkamp et al , 2015 ; Kolb, 2001 ; Puglisi, 2015 ), we have opted to maintain the biological direction as the standard approach in SAINT2.…”