I was wondering why a denatured protein isn't able to fold back into it's native form again.
Because a polypeptide before it's folded has a enthalphy and entropy drive to do so. What does the denaturation process do whith this favouring force to fold into the native structure.
In my opinion I can't see the differences between the unfolded protein (direct after translation) and the denaturated protein.
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$\begingroup$ Some denatured proteins can refold into their native state, although at varying rates. The classic (if slightly dubious) Anfinsen experiment demonstrated that. (see e.g. sandwalk.blogspot.co.uk/2007/02/…) $\endgroup$– DavidCommented Sep 9, 2016 at 16:54
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In short: the unfolded state is a high-energy state of the protein, which will move towards lower-energy states. Some of these states are the folded protein, while others states are denatured protein (forming "wrong" interactions with itself or other proteins). Energy barriers between these states keep the protein in the denatured state even though the folded state might me more favorable.
Or in other words: it's trapped in the denatured state because of kinetics, even though thermodynamics would favor the folded state.
A nice figure to illustrate this: http://www.ghrnet.org/index.php/jbmbr/article/viewFile/1027/1397/6798
If you go into a little bit more detail, you will find that a lot of proteins (especially larger ones) are usually folded by chaperones. These helper proteins will bind to the emerging protein chain to prevent it from aggregating. In a sense they guide the protein to a folded state. In a similar way, chaperones can help proteins overcome the energy bariers that normally prevent it from going from an aggregated state to a folded state.
This review in Science is very complete, but also contains some nice figures that give you an idea of what happens: http://science.sciencemag.org/content/353/6294/aac4354.long /
If you're a pirate: http://science.sciencemag.org.sci-hub.bz/content/353/6294/aac4354.long
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$\begingroup$ You have not explained how the 'energy landscape' differs between the newly synthesized protein (which folds) and the denatured protein (which may or may not fold). $\endgroup$– DavidCommented Sep 9, 2016 at 16:51
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$\begingroup$ Any discussion about protein folding also needs to include chaperones, without which many newly-synthesized proteins would not be able to fold (or re-fold after some sort of conformational "damage"). $\endgroup$– MattDMoCommented Sep 10, 2016 at 12:53
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$\begingroup$ There would be only one energy landscape for the protein. Denatured protein in my answer is specifically aggregated denatured protein, as I assume this is what OP is talking about. A perfectly lonely heat-denatured protein would fold just as easily as a freshly synthesized one, but usually this is not the case that's discussed when talking about denatured proteins. $\endgroup$– VonBecheCommented Sep 10, 2016 at 13:04
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$\begingroup$ @MattDMo: I think most proteins fold just fine without chaperones. In bacteria chaperones are all called heat-shock proteins, so to me it seems they're only required under stress. Do you have any sources showing that these chaperones are folding a large proportion of all proteins all the time? $\endgroup$– VonBecheCommented Sep 10, 2016 at 13:07
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$\begingroup$ @VonBeche I'll find you some references in a minute. Yes, many chaperones are called HSPs because that is the context in which they were discovered, but further research has shown their indispensability in the "normal" cellular context (at least in mammalian cells, which I am most familiar with). $\endgroup$– MattDMoCommented Sep 10, 2016 at 13:12