Lattice simulations of cotranslational folding of single domain proteins

Wang, Peiyu; Klimov, Dmitri K.

doi:10.1002/prot.21547

Cited by 18 publications

(15 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of lattice models and MC simulations has a long tradition in the study of protein folding [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], and, more recently, in exploring the related problems of co-translational folding [36], protein aggregation [37] and binding [38], just to mention a few examples. A main advantage of these minimalistic models over alternative off-lattice representations is their computational efficiency.…”

Section: Introductionmentioning

confidence: 99%

How Difficult Is It to Fold a Knotted Protein? In Silico Insights from Surface-Tethered Folding Experiments

Soler

Faísca

2012

PLoS ONE

View full text Add to dashboard Cite

We explore the effect of surface tethering on the folding process of a lattice protein that contains a trefoil knot in its native structure via Monte Carlo simulations. We show that the outcome of the tethering experiment depends critically on which terminus is used to link the protein to a chemically inert plane. In particular, if surface tethering occurs at the bead that is closer to the knotted core the folding rate becomes exceedingly slow and the protein is not able to find the native structure in all the attempted folding trajectories. Such low folding efficiency is also apparent from the analysis of the probability of knot formation, pknot, as a function of nativeness. Indeed, pknot increases abruptly from ∼0 to ∼1 only when the protein has more than 80% of its native contacts formed, showing that a highly compact conformation must undergo substantial structural re-arrangement in order to get effectively knotted. When the protein is surface tethered by the bead that is placed more far away from the knotted core pknot is higher than in the other folding setups (including folding in the bulk), especially if conformations are highly native-like. These results show that the mobility of the terminus closest to the knotted core is critical for successful folding of trefoil proteins, which, in turn, highlights the importance of a knotting mechanism that is based on a threading movement of this terminus through a knotting loop. The results reported here predict that if this movement is blocked, knotting occurs via an alternative mechanism, the so-called spindle mechanism, which is prone to misfolding. Our simulations show that in the three considered folding setups the formation of the knot is typically a late event in the folding process. We discuss the implications of our findings for co-translational folding of knotted trefoils.

show abstract

Section: Introductionmentioning

confidence: 99%

How Difficult Is It to Fold a Knotted Protein? In Silico Insights from Surface-Tethered Folding Experiments

Soler

Faísca

2012

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Computational models have provided evidence that nascent chains may adopt partial structures similar to the corresponding parts of the complete protein [52]. Other lattice studies present a differing view of cotranslation where nascent peptides can remain largely unstructured until the final stages of synthesis (estimated to be when 90% or more of the protein has been extruded) [53]. This finding is dependent on the involvement of the C-terminal in tertiary interactions, and may not be applicable to all proteins.…”

Section: Introductionmentioning

confidence: 99%

“…This finding is dependent on the involvement of the C-terminal in tertiary interactions, and may not be applicable to all proteins. There is also evidence arising from lattice models that cotranslational folding pathways and refolding pathways are different [53]. Computational simulations of real proteins folding cotranslationally compared to refolding from a denatured state show mixed results.…”

Section: Introductionmentioning

confidence: 99%

Directionality in protein fold prediction

et al. 2010

View full text Add to dashboard Cite

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.

show abstract

“…In the Monte Carlo simulations of three elongating nascent chains modeled on a lattice, Wang & Klimov (84) showed that long-range tertiary interactions, responsible for stabilizing these proteins' native states, affect cotranslational folding kinetics by slowing it down. The marginal stability of these sequences and the stabilizing, long-range interactions allow folding to occur only after more than ∼90% of the protein is synthesized, when the amino acids toward the C terminus become available to form native contacts.…”

Section: Figurementioning

confidence: 99%

Insights into Cotranslational Nascent Protein Behavior from Computer Simulations

Trovato

O’Brien

2016

Annu. Rev. Biophys.

View full text Add to dashboard Cite

Regulation of protein stability and function in vivo begins during protein synthesis, when the ribosome translates a messenger RNA into a nascent polypeptide. Cotranslational processes involving a nascent protein include folding, binding to other macromolecules, enzymatic modification, and secretion through membranes. Experiments have shown that the rate at which the ribosome adds amino acids to the elongating nascent chain influences the efficiency of these processes, with alterations to these rates possibly contributing to diseases, including some types of cancer. In this review, we discuss recent insights into cotranslational processes gained from molecular simulations, how different computational approaches have been combined to understand cotranslational processes at multiple scales, and the new scenarios illuminated by these simulations. We conclude by suggesting interesting questions that computational approaches in this research area can address over the next few years.

show abstract

Lattice simulations of cotranslational folding of single domain proteins

Cited by 18 publications

References 45 publications

How Difficult Is It to Fold a Knotted Protein? In Silico Insights from Surface-Tethered Folding Experiments

How Difficult Is It to Fold a Knotted Protein? In Silico Insights from Surface-Tethered Folding Experiments

Directionality in protein fold prediction

Insights into Cotranslational Nascent Protein Behavior from Computer Simulations

Contact Info

Product

Resources

About