Editing Protein folding (section)

==== Hydrophobic effect ====
[[Image:Protein folding schematic.png|thumb|181x181px|[[Hydrophobic collapse]]. In the compact fold (to the right), the hydrophobic amino acids (shown as black spheres) collapse toward the center to become shielded from aqueous environment.|left]]

Protein folding must be thermodynamically favorable within a cell in order for it to be a spontaneous reaction. Since it is known that protein folding is a spontaneous reaction, then it must assume a negative [[Gibbs free energy]] value. Gibbs free energy in protein folding is directly related to [[enthalpy]] and [[entropy]].<ref name="Voet_2016" /> For a negative delta G to arise and for protein folding to become thermodynamically favorable, then either enthalpy, entropy, or both terms must be favorable.

[[File:Molecular Dynamics Simulation of the Hydrophobic Solvation of Argon.webm|thumb|Entropy is decreased as the water molecules become more orderly near the hydrophobic solute.|262x262px]]

Minimizing the number of hydrophobic side-chains exposed to water is an important driving force behind the folding process.<ref name="Pace">{{cite journal | vauthors = Pace CN, Shirley BA, McNutt M, Gajiwala K | title = Forces contributing to the conformational stability of proteins | journal = FASEB Journal | volume = 10 | issue = 1 | pages = 75–83 | date = January 1996 | pmid = 8566551 | doi = 10.1096/fasebj.10.1.8566551 | doi-access = free | s2cid = 20021399 }}</ref> The hydrophobic effect is the phenomenon in which the hydrophobic chains of a protein collapse into the core of the protein (away from the hydrophilic environment).<ref name="Voet_2016" /> In an aqueous environment, the water molecules tend to aggregate around the hydrophobic regions or side chains of the protein, creating water shells of ordered water molecules.<ref>{{cite journal | vauthors = Cui D, Ou S, Patel S | title = Protein-spanning water networks and implications for prediction of protein–protein interactions mediated through hydrophobic effects | journal = Proteins | volume = 82 | issue = 12 | pages = 3312–26 | date = December 2014 | pmid = 25204743 | doi = 10.1002/prot.24683 | s2cid = 27113763 }}</ref> An ordering of water molecules around a hydrophobic region increases order in a system and therefore contributes a negative change in entropy (less entropy in the system). The water molecules are fixed in these water cages which drives the [[hydrophobic collapse]], or the inward folding of the hydrophobic groups. The hydrophobic collapse introduces entropy back to the system via the breaking of the water cages which frees the ordered water molecules.<ref name="Voet_2016" /> The multitude of hydrophobic groups interacting within the core of the globular folded protein contributes a significant amount to protein stability after folding, because of the vastly accumulated van der Waals forces (specifically [[London dispersion force|London Dispersion forces]]).<ref name="Voet_2016" /> The [[hydrophobic effect]] exists as a driving force in thermodynamics only if there is the presence of an aqueous medium with an [[amphiphilic]] molecule containing a large hydrophobic region.<ref>{{cite journal | vauthors = Tanford C | title = The hydrophobic effect and the organization of living matter | journal = Science | volume = 200 | issue = 4345 | pages = 1012–8 | date = June 1978 | pmid = 653353 | doi = 10.1126/science.653353 | bibcode = 1978Sci...200.1012T }}</ref> The strength of hydrogen bonds depends on their environment; thus, H-bonds enveloped in a hydrophobic core contribute more than H-bonds exposed to the aqueous environment to the stability of the native state.<ref name="Deechongkit">{{cite journal | vauthors = Deechongkit S, Nguyen H, Powers ET, Dawson PE, Gruebele M, Kelly JW | title = Context-dependent contributions of backbone hydrogen bonding to beta-sheet folding energetics | journal = Nature | volume = 430 | issue = 6995 | pages = 101–5 | date = July 2004 | pmid = 15229605 | doi = 10.1038/nature02611 | bibcode = 2004Natur.430..101D | s2cid = 4315026 }}</ref>

In proteins with globular folds, hydrophobic amino acids tend to be interspersed along the primary sequence, rather than randomly distributed or clustered together.<ref>{{cite journal | vauthors = Irbäck A, Sandelin E | title = On hydrophobicity correlations in protein chains | journal = Biophysical Journal | volume = 79 | issue = 5 | pages = 2252–8 | date = November 2000 | pmid = 11053106 | pmc = 1301114 | doi = 10.1016/S0006-3495(00)76472-1 | arxiv = cond-mat/0010390 | bibcode = 2000BpJ....79.2252I }}</ref><ref>{{cite journal | vauthors = Irbäck A, Peterson C, Potthast F | title = Evidence for nonrandom hydrophobicity structures in protein chains | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 18 | pages = 9533–8 | date = September 1996 | pmid = 8790365 | pmc = 38463 | doi = 10.1073/pnas.93.18.9533 | arxiv = chem-ph/9512004 | bibcode = 1996PNAS...93.9533I | doi-access = free }}</ref> However, proteins that have recently been born [[De novo gene birth|de novo]], which tend to be [[intrinsically disordered proteins|intrinsically disordered]],<ref>{{cite journal | vauthors = Wilson BA, Foy SG, Neme R, Masel J | title = De Novo Gene Birth | journal = Nature Ecology & Evolution | volume = 1 | issue = 6 | pages = 0146–146 | date = June 2017 | pmid = 28642936 | pmc = 5476217 | doi = 10.1038/s41559-017-0146 | bibcode = 2017NatEE...1..146W }}</ref><ref>{{cite journal | vauthors = Willis S, Masel J | title = Gene Birth Contributes to Structural Disorder Encoded by Overlapping Genes | journal = Genetics | volume = 210 | issue = 1 | pages = 303–313 | date = September 2018 | pmid = 30026186 | pmc = 6116962 | doi = 10.1534/genetics.118.301249 }}</ref> show the opposite pattern of hydrophobic amino acid clustering along the primary sequence.<ref>{{cite journal | vauthors = Foy SG, Wilson BA, Bertram J, Cordes MH, Masel J | title = A Shift in Aggregation Avoidance Strategy Marks a Long-Term Direction to Protein Evolution | journal = Genetics | volume = 211 | issue = 4 | pages = 1345–1355 | date = April 2019 | pmid = 30692195 | pmc = 6456324 | doi = 10.1534/genetics.118.301719 }}</ref>