Following up on last week’s entry, this post will explore the same topic: polypeptide chains assuming native-like conformations as they are extruded from the ribosome, or for the less intimate with the concept, co-translational protein folding.
Before addressing some important questions concerning co-translational protein folding, I would like to make a parenthesis: I want to dedicate a paragraph or two to talk about time.
Biological processes are dynamic. They are events that occur over a period of time. For instance, one can quantify the effect of mutations propagated and accumulated over millions of years of evolution. One can also quantify the femtoseconds in which subtle conformational changes occur in photoreceptor proteins like rhodopsin, when they respond to light. Time is fundamental to understand and model any sort of biological event.
Albeit it might seem obvious to the reader that time is so crucial to amass biological knowledge, those of us more theoretically inclined (bioinformaticians, computational biologists, biostatisticians, mathematical biologists and so on and so forth) are usually presented with models that tend to over-simplify reality. Surprisingly enough, there are many over-simplistic models that neglect the effect of time in order to “better” represent whatever they claim to model. Take Protein Docking for instance. The biological process at hand presents a complicated dynamic. There is a kinetic equilibrium, in which a vast amount of protein and ligand molecules interact, associating into complexes and dissociating. Nonetheless, Protein Docking is traditionally reduced to the binding affinity between a pair of molecules. As one might say, this is only a problem if I can present a solution… Luckily, Protein Docking is not my subject of expertise, so I will leave this question open to more tenacious minds than my own.
One of the areas in which I am truly interested in is the co-translational aspect of protein folding. If one performs a quick Google Images search, using the terms “Protein Synthesis” or “Protein Translation”, the results tell a very interesting story. The vast majority of nascent protein chains are represented as fully elongates peptide chains. In a majority of pictures, the growing peptides do not even present secondary structure. They are mostly represented by long, unfolded, almost linear polymers.
Now, any first year Biochemistry student learns about something called Hydrophobicity (or hydrophilicity depending on whether you are a glass half empty or half full type of person). It is biochemistry-introductory-text-book stuff that some residues are polar and some residues are apolar, and hence will hide from water, forming a hydrophobic core. That (hydrophobicity) is one of the main driving forces of protein folding.
Hence, most of the images that appear in our Google Images search are not very representative. They are plain wrong. It is simple physics that the growing peptide chains will form secondary and tertiary structures during the process of protein synthesis. One has to remember that this process is dynamic, it is happening over time. Under these circumstances, time should not be neglected. The time scale at which extrusion occurs is slow enough to allow the nascent chain to probe conformations and simply abide to the laws of physics. A fully elongated, completely unfolded and denatured peptide chain would not exist during protein synthesis. These nascent chains would adopt intermediate conformations simply as a result of apolar residues trying to hide from water.
Ok. Now, the BIG question that can be raised is whether those intermediate conformations actually resemble the native state of the fully elongated protein. I do not want to incur in Baby Kicking, but one thing that evolution has taught us is that cells have evolved to be highly efficient systems. There is no room for wasted energy. It makes sense to hypothesize that over millions of years, the cellular machinery has adapted to explore these intermediate conformations in order to make the process of protein folding more efficient.
Over the past couple of years, substantial evidence has been amassed that codon usage and the degeneracy of the genetic code could be exploited by cells to ensure that protein folding occurs accurately and efficiently. There are many theoretical ways that such exploitation could occur: the codon translation speed could facilitate the formation of certain intermediates that are beneficial for protein folding, that increase stability or that prevent protein aggregation. There is even a biomedical impact given that some observed pathologies have been associated with synonymous codon mutations that may lead to misfolded proteins.
In the paper I presented during this journal club , O’Brien and colleagues have devised and described a very interesting kinetic model for protein translation. Their model was used to describe possible scenarios in which both fast and slow translation speed codons are coordinators of co-translational protein folding. Please note that, in this context, co-translational protein folding is perceived as an enrichment of intermediate conformations of the nascent chains, which resemble the native structure of the fully elongated protein.
In the model described in the paper, they opted for a probabilistic approach instead of an analytical (differential equations) approach. The time is modelled by the use of probabilities. The authors derived a formula to quantify the expected proportion of nascent chains of a given length that would be in a Folded intermediate state (one that resembles the native structure). They have managed to express this in terms of a rate of codon translation. Therefore, they stablish a direct relationship between Co-Translational protein folding and codon translation speed.
Their analysis is robust as none of the constants and kinetic rates need to be experimentally derived in order to provide insights about the protein folding process. Overall, I think the way the model was built was quite ingenious and very interesting. I would suggest any interested reader to read the article if they want to understand how the whole modelling was carried out.
Overall, I think the authors present a compelling argument for how cells could explore codon degeneracy and co-translational aspects of protein folding to improve folding efficiency. One of their results present a scenario in which fast translation speed codons can be used to assist in the fold of unstable protein regions, preventing the formation of misfolded intermediates.
One of the many functions of mathematical models is to provide insights into the underlying biology of the phenomena they attempt to model. The lack of any experimental evidence to support this paper’s results does not make it any less interesting. The article presents to the readers a sound and solid mathematical argument as to how co-translational aspects of protein folding could be beneficial for cell efficiency. If anything, they provide interesting hypotheses that might drive experimentalists in the future.