Directionality in protein fold prediction.

BACKGROUND: Ever since the ground-breaking work of Anfinsen et al. in which a denatured protein was found to refold to its native state, it has been frequently stated by the protein fold prediction community that all the information required for protein folding lies in the amino acid sequence. Recent in vitro experiments and in silico computational studies, however, have shown that cotranslation may affect the folding pathway of some proteins, especially those of ancient folds. In this paper aspects of cotranslational folding have been incorporated into a protein structure prediction algorithm by adapting the Rosetta program to fold proteins as the nascent chain elongates. This makes it possible to conduct a pairwise comparison of folding accuracy, by comparing folds created sequentially from each end of the protein. RESULTS: A single main result emerged: in 94% of proteins analyzed, following the sense of translation, from N-terminus to C-terminus, produced better predictions than following the reverse sense of translation, from the C-terminus to N-terminus. Two secondary results emerged. First, this superiority of N-terminus to C-terminus folding was more marked for proteins showing stronger evidence of cotranslation and second, an algorithm following the sense of translation produced predictions comparable to, and occasionally better than, Rosetta. CONCLUSIONS: There is a directionality effect in protein fold prediction. At present, prediction methods appear to be too noisy to take advantage of this effect; as techniques refine, it may be possible to draw benefit from a sequential approach to protein fold prediction.

Cotranslational protein folding--fact or fiction?

MOTIVATION: Experimentalists have amassed extensive evidence over the past four decades that proteins appear to fold during production by the ribosome. Protein structure prediction methods, however, do not incorporate this property of folding. A thorough study to find the fingerprint of such sequential folding is the first step towards using it in folding algorithms, so assisting structure prediction. RESULTS: We explore computationally the existence of evidence for cotranslational folding, based on large sets of experimentally determined structures in the PDB. Our perspective is that cotranslational folding is the norm, but that the effect is masked in most classes. We show that it is most evident in alpha/beta proteins, confirming recent findings. We also find mild evidence that older proteins may fold cotranslationally. A tool is provided for determining, within a protein, where cotranslation is most evident.

Modelling sequential protein folding under kinetic control.

MOTIVATION: This study presents a novel investigation of the effect of kinetic control on cotranslational protein folding. We demonstrate the effect using simple HP lattice models and show that the cotranslational folding of proteins under kinetic control has a significant impact on the final conformation. Differences arise if nature is not capable of pushing a partially folded protein back over a large energy barrier. For this reason we argue that such constraints should be incorporated into structure prediction techniques. We introduce a finite surmountable energy barrier which allows partially formed chains to partly unfold, and permits us to enumerate exhaustively all energy pathways. RESULTS: We compare the ground states obtained sequentially with the global ground states of designing sequences (those with a unique global ground state). We find that the sequential ground states become less numerous and more compact as the surmountable energy barrier increases. We also introduce a probabilistic model to describe the distribution of final folds and allow partial settling to the Boltzmann distribution of states at each stage. As a result, conformations with the highest probability of final occurrence are not necessarily the ones of lowest energy. AVAILABILITY: Software available on request.