Editing Protein design (section)

==Overview and history==
The goal in rational protein design is to predict [[amino acid]] [[Protein primary structure|sequences]] that will [[protein folding|fold]] to a specific protein structure. Although the number of possible protein sequences is vast, growing exponentially with the size of the protein chain, only a subset of them will fold reliably and quickly to one [[native state]]. Protein design involves identifying novel sequences within this subset. The native state of a protein is the conformational [[Thermodynamic free energy|free energy]] minimum for the chain. Thus, protein design is the search for sequences that have the chosen structure as a free energy minimum. In a sense, it is the reverse of [[protein structure prediction]]. In design, a [[Protein tertiary structure|tertiary structure]] is specified, and a sequence that will fold to it is identified. Hence, it is also termed ''inverse folding''. Protein design is then an optimization problem: using some scoring criteria, an optimized sequence that will fold to the desired structure is chosen.

When the first proteins were rationally designed during the 1970s and 1980s, the sequence for these was optimized manually based on analyses of other known proteins, the sequence composition, amino acid charges, and the geometry of the desired structure.<ref name="richardson1989" /> The first designed proteins are attributed to Bernd Gutte, who designed a reduced version of a known catalyst, bovine ribonuclease, and tertiary structures consisting of beta-sheets and alpha-helices, including a binder of [[DDT]]. Urry and colleagues later designed [[elastin]]-like [[fibrous protein|fibrous]] peptides based on rules on sequence composition. Richardson and coworkers designed a 79-residue protein with no sequence homology to a known protein.<ref name="richardson1989" /> In the 1990s, the advent of powerful computers, [[Conformational isomerism#Protein rotamer libraries|libraries of amino acid conformations]], and force fields developed mainly for [[molecular dynamics]] simulations enabled the development of structure-based computational protein design tools. Following the development of these computational tools, great success has been achieved over the last 30 years in protein design. The first protein successfully designed completely ''de novo'' was done by [[Stephen Mayo]] and coworkers in 1997,<ref name="dahiyat1997" /> and, shortly after, in 1999 [[Peter S. Kim]] and coworkers designed dimers, trimers, and tetramers of unnatural right-handed [[coiled coil]]s.<ref name="gordon99review">{{cite journal|last=Gordon|first=DB|author2=Marshall, SA |author3=Mayo, SL |title=Energy functions for protein design.|journal=Current Opinion in Structural Biology|date=August 1999|volume=9|issue=4|pages=509–13|pmid=10449371|doi=10.1016/s0959-440x(99)80072-4}}</ref><ref name="harbury99">{{cite journal|last=Harbury|first=PB|author2=Plecs, JJ |author3=Tidor, B |author4=Alber, T |author5= Kim, PS |title=High-resolution protein design with backbone freedom.|journal=Science|date=November 20, 1998|volume=282|issue=5393|pages=1462–7|pmid=9822371|doi=10.1126/science.282.5393.1462}}</ref> In 2003, [[David Baker (biochemist)|David Baker]]'s laboratory designed a full protein to a fold never seen before in nature.<ref name="kuhlman03" /> Later, in 2008, Baker's group computationally designed enzymes for two different reactions.<ref>{{cite journal|last=Sterner|first=R|author2=Merkl, R |author3=Raushel, FM |title=Computational design of enzymes.|journal=Chemistry & Biology|date=May 2008|volume=15|issue=5|pages=421–3|pmid=18482694|doi=10.1016/j.chembiol.2008.04.007|doi-access=free}}</ref> In 2010, one of the most powerful broadly neutralizing antibodies was isolated from patient serum using a computationally designed protein probe.<ref name="wu2010a">{{cite journal|last1=Wu|first1=X|author2=Yang, ZY|author3=Li, Y|author4=Hogerkorp, CM|author5=Schief, WR|author6=Seaman, MS|author7=Zhou, T|author8=Schmidt, SD|author9=Wu, L|author10=Xu, L|author11=Longo, NS|author12=McKee, K|author13=O'Dell, S|author14=Louder, MK|author15=Wycuff, DL|author16=Feng, Y|author17=Nason, M|author18=Doria-Rose, N|author19=Connors, M|author20=Kwong, PD|author21=Roederer, M|author22=Wyatt, RT|author23=Nabel, GJ|author23-link=Gary Nabel|author24=Mascola, JR|author24-link=John R. Mascola |title=Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1.|journal=Science|date=August 13, 2010|volume=329|issue=5993|pages=856–61|pmid=20616233|bibcode= 2010Sci...329..856W |doi= 10.1126/science.1187659|pmc=2965066}}</ref> In 2024, Baker received one half of the [[Nobel Prize in Chemistry]] for his advancement of computational protein design, with the other half being shared by [[Demis Hassabis]] and [[John M. Jumper|John Jumper]] of [[Google DeepMind|Deepmind]] for protein structure prediction.<ref>{{Cite web |date=2024-10-09 |title=Press Release: The Nobel Prize in Chemistry 2024 |url=https://www.nobelprize.org/prizes/chemistry/2024/press-release/ |url-status=live |access-date=2025-03-31 |website=Nobel Prize}}</ref> Due to these and other successes (e.g., see [[#Applications and examples of designed proteins|examples]] below), protein design has become one of the most important tools available for [[protein engineering]]. There is great hope that the design of new proteins, small and large, will have uses in [[biomedicine]] and [[bioengineering]].
<!--[[Prion]] diseases like [[bovine spongiform encephalopathy]] (mad-cow disease) illustrate how important it is that designer proteins possess only one stable conformation. In mad-cow disease, there exists a healthy protein with a fatal weakness: There is another conformation that it can "comfortably" take; the abnormally folded shape has very little free energy and is thus very stable. For reasons that are not yet fully understood, this [[Protein misfolding|mis-folded]] prion protein can [[Catalysis|catalyze]] other proteins of its type to also adopt the mis-folded shape, causing a disease-generating cascade of formerly functional proteins to quickly mis-fold. They lose the ability to perform their intended function in the new conformation, and have a tendency to form aggregates called [[senile plaques]]. The buildup of these aggregates in the brain leads to progressive neuronal death, and eventually death of the entire organism. Thus, it is easy to see the importance both that a designer protein have only one possible stable tertiary structure and that researchers exercise extreme diligence to ensure that this remain the case in all environments, especially ''[[in vivo]]''.-->