Directionality in protein fold prediction

Abstract

BackgroundEver 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.ResultsA 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.ConclusionsThere 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.

Ligand-Driven Vectorial Folding of Ribosome-Bound Human CFTR NBD1

“…Folding of N-terminal and C-terminal regions of NBD1 are therefore separated both spatially and temporally during synthesis. These data support a model predicted by in silico topological accessibility studies in which ancient α/β class proteins preferentially initiate directional protein folding via local N-terminal contacts (Ellis et al, 2010). …”

Cotranslational Protein Folding and Terminus Hydrophobicity

“…The curve shown is a lowess plot through the data based on 68 protein chains taken from [17]. Terminals comprised the first 10 (N-terminus) and last 10 (C-terminus) residues in the sequence.…”

Approaches toab initiomolecular replacement of α-helical transmembrane proteins

“…Ab initio protein-structure prediction is the process of determining the tertiary structure of a protein starting purely from its sequence, and not relying on the use of an existing structure as a template. Popular examples of ab initio modelling software include ROSETTA, QUARK and SAINT2 (Simons et al, 1997;Rohl et al, 2004;Xu et al, 2012;Ellis et al, 2010). Ab initio modelling for globular proteins, however, is accurate only for modest chain lengths.…”