Editing Protein folding (section)

=== Energy landscape of protein folding ===
[[File:Folding funnel schematic.svg|thumb|286x286px|The energy funnel by which an unfolded polypeptide chain assumes its native structure]]
The [[Configuration space (physics)|configuration space]] of a protein during folding can be visualized as an [[energy landscape]]. According to Joseph Bryngelson and [[Peter Wolynes]], proteins follow the ''principle of minimal frustration'', meaning that naturally evolved proteins have optimized their folding energy landscapes,<ref name="bryngelson">{{cite journal | vauthors = Bryngelson JD, Onuchic JN, Socci ND, Wolynes PG | title = Funnels, pathways, and the energy landscape of protein folding: a synthesis | journal = Proteins | volume = 21 | issue = 3 | pages = 167–95 | date = March 1995 | pmid = 7784423 | doi = 10.1002/prot.340210302 | arxiv = chem-ph/9411008 | s2cid = 13838095 }}</ref> and that nature has chosen amino acid sequences so that the folded state of the protein is sufficiently stable. In addition, the acquisition of the folded state had to become a sufficiently fast process. Even though nature has reduced the level of ''frustration'' in proteins, some degree of it remains up to now as can be observed in the presence of local minima in the energy landscape of proteins.

A consequence of these evolutionarily selected sequences is that proteins are generally thought to have globally "funneled energy landscapes" (a term coined by [[José Onuchic]])<ref>{{cite journal | vauthors = Leopold PE, Montal M, Onuchic JN | author-link3 = José Onuchic | title = Protein folding funnels: a kinetic approach to the sequence-structure relationship | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 18 | pages = 8721–5 | date = September 1992 | pmid = 1528885 | pmc = 49992 | doi = 10.1073/pnas.89.18.8721 | bibcode = 1992PNAS...89.8721L | doi-access = free }}</ref> that are largely directed toward the native state. This "[[folding funnel]]" landscape allows the protein to fold to the native state through any of a large number of pathways and intermediates, rather than being restricted to a single mechanism. The theory is supported by both [[lattice protein|computational simulations of model proteins]] and experimental studies,<ref name="bryngelson" /> and it has been used to improve methods for [[protein structure prediction]] and [[protein design|design]].<ref name="bryngelson" /> The description of protein folding by the leveling free-energy landscape is also consistent with the 2nd law of thermodynamics.<ref>{{cite journal |doi=10.1016/j.physa.2008.12.004 |title=Protein folding as an evolutionary process |journal=Physica A: Statistical Mechanics and Its Applications | volume = 388 | issue = 6 | pages = 851–62 | year = 2009 | last1 = Sharma | first1 = Vivek | last2 = Kaila | first2 = Ville R.I. | last3 = Annila | first3 = Arto | name-list-style = vanc  | bibcode = 2009PhyA..388..851S }}</ref> Physically, thinking of landscapes in terms of visualizable potential or total energy surfaces simply with maxima, saddle points, minima, and funnels, rather like geographic landscapes, is perhaps a little misleading. The relevant description is really a high-dimensional phase space in which manifolds might take a variety of more complicated topological forms.<ref name="Robson_2008">{{cite book |doi=10.1016/S0079-6603(08)00405-4 |pmid=19121702 |chapter=Protein Folding Revisited |title=Molecular Biology of Protein Folding, Part B |volume=84 |pages=161–202 |series=Progress in Molecular Biology and Translational Science |year=2008 |last1=Robson |first1=Barry |last2=Vaithilingam |first2=Andy | name-list-style = vanc |isbn=978-0-12-374595-8 }}</ref>

The unfolded polypeptide chain begins at the top of the funnel where it may assume the largest number of unfolded variations and is in its highest energy state. Energy landscapes such as these indicate that there are a large number of initial possibilities, but only a single native state is possible; however, it does not reveal the numerous folding pathways that are possible. A different molecule of the same exact protein may be able to follow marginally different folding pathways, seeking different lower energy intermediates, as long as the same native structure is reached.<ref name="Dill_2012">{{cite journal | vauthors = Dill KA, MacCallum JL | title = The protein-folding problem, 50 years on | journal = Science | volume = 338 | issue = 6110 | pages = 1042–6 | date = November 2012 | pmid = 23180855 | doi = 10.1126/science.1219021 | bibcode = 2012Sci...338.1042D | s2cid = 5756068 }}</ref> Different pathways may have different frequencies of utilization depending on the thermodynamic favorability of each pathway. This means that if one pathway is found to be more thermodynamically favorable than another, it is likely to be used more frequently in the pursuit of the native structure.<ref name="Dill_2012" /> As the protein begins to fold and assume its various conformations, it always seeks a more thermodynamically favorable structure than before and thus continues through the energy funnel. Formation of secondary structures is a strong indication of increased stability within the protein, and only one combination of secondary structures assumed by the polypeptide backbone will have the lowest energy and therefore be present in the native state of the protein.<ref name="Dill_2012" /> Among the first structures to form once the polypeptide begins to fold are alpha helices and beta turns, where alpha helices can form in as little as 100 nanoseconds and beta turns in 1 microsecond.<ref name="Dobson_2003">{{cite journal | vauthors = Dobson CM | title = Protein folding and misfolding | journal = Nature | volume = 426 | issue = 6968 | pages = 884–90 | date = December 2003 | pmid = 14685248 | doi = 10.1038/nature02261 | bibcode = 2003Natur.426..884D | s2cid = 1036192 }}</ref>

There exists a saddle point in the energy funnel landscape where the [[transition state]] for a particular protein is found.<ref name="Dobson_2003" /> The transition state in the energy funnel diagram is the conformation that must be assumed by every molecule of that protein if the protein wishes to finally assume the native structure. No protein may assume the native structure without first passing through the transition state.<ref name="Dobson_2003" /> The transition state can be referred to as a variant or premature form of the native state rather than just another intermediary step.<ref name="Fersht_2000">{{cite journal | vauthors = Fersht AR | title = Transition-state structure as a unifying basis in protein-folding mechanisms: contact order, chain topology, stability, and the extended nucleus mechanism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 4 | pages = 1525–9 | date = February 2000 | pmid = 10677494 | pmc = 26468 | doi = 10.1073/pnas.97.4.1525 | bibcode = 2000PNAS...97.1525F | doi-access = free }}</ref> The folding of the transition state is shown to be rate-determining, and even though it exists in a higher energy state than the native fold, it greatly resembles the native structure. Within the transition state, there exists a nucleus around which the protein is able to fold, formed by a process referred to as "nucleation condensation" where the structure begins to collapse onto the nucleus.<ref name="Fersht_2000" />