On 2016 Apr 03, Ariel Fernandez commented:

Protein folding in vitro is a spontaneous process [1]. This means it is irreversible in the thermodynamic sense [2]. The endpoints of the folding process, the native state and the denatured ensemble, may be recovered by restoring renaturing or denaturing conditions, respectively. Thus, at a variance with thermodynamics, this is what protein scientists usually mean when they claim that protein folding is reversible [1]. On the other hand, according to the tenets of thermodynamics, the folding and unfolding pathways themselves are untraceable and irreproducible [2]. In fact the very notion of “pathway” for a spontaneous process is thermodynamically meaningless or at least questionable. Dissipative forces intervene in the folding process producing a net increase in the entropy of the universe, and this is the hallmark of irreversibility. Therefore, the intermediate states associated with the folding process are irretrievable, as it would be the case for any spontaneous process in nature or in the lab.

Notwithstanding these thermodynamic considerations, a very active quest for folding intermediates continues to this day [3]. This search may be futile, probably meaningless from a thermodynamic perspective, unless some sort of paradox holds that, at the very least, needs to be properly dispelled. To the best of my knowledge this has not been done. Real folding intermediates are not only very difficult to trap: they do not exist per se, plain and simple. Any claim to the contrary inevitably violates the second law of thermodynamics.

Even more puzzling are the efforts to characterize folding intermediates by denaturing the native state (however carefully [4]). As the second law of thermodynamics tells us, the denaturation process is not the reverse of the folding process: only the endpoints are reversed. To discourage efforts in this direction, it would be more eloquent to resort to an analogy. Imagine you need to describe the way a standing house has been put together. No one in his/her right mind would address the problem by having the house demolished (however carefully), taking snapshots at different stages of demolition and then playing the movie backwards. Yet, intriguingly, a similar reasoning has been assumed to hold mutatis mutandis in the context of protein folding [5]. This accumulation of seeming contradictions may well lead to a paradox - and thermodynamics is full of those - and at the very least the paradox demands proper clarification in thermodynamic terms before the saga for the quest of folding intermediates continues. Ariel Fernandez

References

1. Anfinsen, C.B. Science 181, 223-230 (1973).

2. Planck, M. Treatise on Thermodynamics, 3rd edition, Dover, New York (2010).

3. Vendruscolo M. & Dobson, C.M. Nature Chem. Biol. 9, 216-217 (2013).

4. Jaremko, M., Jaremko, Ł., Kim, H.Y., Cho, M.K., Schwieters, C.D., Giller, K., Becker, S. & Zweckstetter, M. Nature Chem. Biol. 9, 264-270 (2013).

5. Fernandez, A. Biomolecular Interfaces (ISBN 978-3-319-16849-4), Springer, Berlin (2015).

On 2016 Apr 03, Ariel Fernandez commented:

Protein folding in vitro is a spontaneous process [1]. This means it is irreversible in the thermodynamic sense [2]. The endpoints of the folding process, the native state and the denatured ensemble, may be recovered by restoring renaturing or denaturing conditions, respectively. Thus, at a variance with thermodynamics, this is what protein scientists usually mean when they claim that protein folding is reversible [1]. On the other hand, according to the tenets of thermodynamics, the folding and unfolding pathways themselves are untraceable and irreproducible [2]. In fact the very notion of “pathway” for a spontaneous process is thermodynamically meaningless or at least questionable. Dissipative forces intervene in the folding process producing a net increase in the entropy of the universe, and this is the hallmark of irreversibility. Therefore, the intermediate states associated with the folding process are irretrievable, as it would be the case for any spontaneous process in nature or in the lab.

Notwithstanding these thermodynamic considerations, a very active quest for folding intermediates continues to this day [3]. This search may be futile, probably meaningless from a thermodynamic perspective, unless some sort of paradox holds that, at the very least, needs to be properly dispelled. To the best of my knowledge this has not been done. Real folding intermediates are not only very difficult to trap: they do not exist per se, plain and simple. Any claim to the contrary inevitably violates the second law of thermodynamics.

Even more puzzling are the efforts to characterize folding intermediates by denaturing the native state (however carefully [4]). As the second law of thermodynamics tells us, the denaturation process is not the reverse of the folding process: only the endpoints are reversed. To discourage efforts in this direction, it would be more eloquent to resort to an analogy. Imagine you need to describe the way a standing house has been put together. No one in his/her right mind would address the problem by having the house demolished (however carefully), taking snapshots at different stages of demolition and then playing the movie backwards. Yet, intriguingly, a similar reasoning has been assumed to hold mutatis mutandis in the context of protein folding [5]. This accumulation of seeming contradictions may well lead to a paradox - and thermodynamics is full of those - and at the very least the paradox demands proper clarification in thermodynamic terms before the saga for the quest of folding intermediates continues. Ariel Fernandez

References

1. Anfinsen, C.B. Science 181, 223-230 (1973).

2. Planck, M. Treatise on Thermodynamics, 3rd edition, Dover, New York (2010).

3. Vendruscolo M. & Dobson, C.M. Nature Chem. Biol. 9, 216-217 (2013).

4. Jaremko, M., Jaremko, Ł., Kim, H.Y., Cho, M.K., Schwieters, C.D., Giller, K., Becker, S. & Zweckstetter, M. Nature Chem. Biol. 9, 264-270 (2013).

5. Fernandez, A. Biomolecular Interfaces (ISBN 978-3-319-16849-4), Springer, Berlin (2015).