Editing Hemoprotein (section)

==Designed heme proteins==

[[File:Pincer-1_beta_heme_peptide.png|thumb|260 px| Pincer-1:<ref name=":0">{{cite journal | vauthors = Nagarajan D, Sukumaran S, Deka G, Krishnamurthy K, Atreya HS, Chandra N | title = Design of a heme-binding peptide motif adopting a β-hairpin conformation | language = English | journal = The Journal of Biological Chemistry | volume = 293 | issue = 24 | pages = 9412–9422 | date = June 2018 | pmid = 29695501 | pmc = 6005436 | doi = 10.1074/jbc.RA118.001768 | doi-access = free }}</ref> A designed heme-binding peptide adopting an all-beta secondary structure.  ABOVE: Topological representation of Pincer-1 showing the secondary structure and designed interacting residues.  BELOW: All-atom 3-dimensional model of Pincer-1. This model was partially confirmed using [[Nuclear Magnetic Resonance|NMR]]. ]]

Due to the diverse functions of the heme molecule: as an electron transporter, an oxygen carrier, and as an enzyme cofactor, heme binding proteins have consistently attracted the attention of protein designers. Initial design attempts focused on α-helical heme binding proteins, in part, due to the relative simplicity of designing self-assembling helical bundles. Heme binding sites were designed inside the inter-helical hydrophobic grooves. Examples of such designs include:
* Helichrome<ref>{{Cite journal | vauthors = Sasaki T, Kaiser ET |date=1989-01-01 |title=Helichrome: synthesis and enzymic activity of a designed hemeprotein |journal=Journal of the American Chemical Society |language=en |volume=111 |issue=1 |pages=380–381 |doi=10.1021/ja00183a065 |issn=0002-7863}}</ref><ref>{{cite journal | vauthors = Sasaki T, Kaiser ET | title = Synthesis and structural stability of helichrome as an artificial hemeproteins | journal = Biopolymers | volume = 29 | issue = 1 | pages = 79–88 | date = January 1990 | pmid = 2328295 | doi = 10.1002/bip.360290112 | s2cid = 35536899 }}</ref>
* Globin-1<ref>{{cite journal | vauthors = Isogai Y, Ota M, Fujisawa T, Izuno H, Mukai M, Nakamura H, Iizuka T, Nishikawa K | display-authors = 6 | title = Design and synthesis of a globin fold | journal = Biochemistry | volume = 38 | issue = 23 | pages = 7431–7443 | date = June 1999 | pmid = 10360940 | doi = 10.1021/bi983006y }}</ref>
* Cy-AA-EK<ref>{{cite journal | vauthors = Rosenblatt MM, Wang J, Suslick KS | title = De novo designed cyclic-peptide heme complexes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 23 | pages = 13140–13145 | date = November 2003 | pmid = 14595023 | pmc = 263730 | doi = 10.1073/pnas.2231273100 | bibcode = 2003PNAS..10013140R | doi-access = free }}</ref>
* Peptides IIa/IId<ref>{{cite journal | vauthors = Robertson DE, Farid RS, Moser CC, Urbauer JL, Mulholland SE, Pidikiti R, Lear JD, Wand AJ, DeGrado WF, Dutton PL | display-authors = 6 | title = Design and synthesis of multi-haem proteins | journal = Nature | volume = 368 | issue = 6470 | pages = 425–432 | date = March 1994 | pmid = 8133888 | doi = 10.1038/368425a0 | bibcode = 1994Natur.368..425R | s2cid = 4360174 }}</ref>
* α2<ref>{{Cite journal | vauthors = Choma CT, Lear JD, Nelson MJ, Dutton PL, Robertson DE, DeGrado WF |date=1994-02-01 |title=Design of a heme-binding four-helix bundle |journal=Journal of the American Chemical Society |language=en |volume=116 |issue=3 |pages=856–865 |doi=10.1021/ja00082a005 |issn=0002-7863}}</ref>
* Transmembrane helical designs<ref>{{cite journal | vauthors = Discher BM, Noy D, Strzalka J, Ye S, Moser CC, Lear JD, Blasie JK, Dutton PL | display-authors = 6 | title = Design of amphiphilic protein maquettes: controlling assembly, membrane insertion, and cofactor interactions | journal = Biochemistry | volume = 44 | issue = 37 | pages = 12329–12343 | date = September 2005 | pmid = 16156646 | pmc = 2574520 | doi = 10.1021/bi050695m }}</ref><ref>{{cite journal | vauthors = Mahajan M, Bhattacharjya S | title = Designed di-heme binding helical transmembrane protein | journal = ChemBioChem | volume = 15 | issue = 9 | pages = 1257–1262 | date = June 2014 | pmid = 24829076 | doi = 10.1002/cbic.201402142 | s2cid = 20982919 }}</ref><ref>{{cite journal | vauthors = Korendovych IV, Senes A, Kim YH, Lear JD, Fry HC, Therien MJ, Blasie JK, Walker FA, Degrado WF | display-authors = 6 | title = De novo design and molecular assembly of a transmembrane diporphyrin-binding protein complex | journal = Journal of the American Chemical Society | volume = 132 | issue = 44 | pages = 15516–15518 | date = November 2010 | pmid = 20945900 | pmc = 3016712 | doi = 10.1021/ja107487b }}</ref>

Later design attempts focused on creating functional heme binding helical bundles, such as:
* [[Oxidoreductase]]s<ref name=":1">{{cite journal | vauthors = Farid TA, Kodali G, Solomon LA, Lichtenstein BR, Sheehan MM, Fry BA, Bialas C, Ennist NM, Siedlecki JA, Zhao Z, Stetz MA, Valentine KG, Anderson JL, Wand AJ, Discher BM, Moser CC, Dutton PL | display-authors = 6 | title = Elementary tetrahelical protein design for diverse oxidoreductase functions | journal = Nature Chemical Biology | volume = 9 | issue = 12 | pages = 826–833 | date = December 2013 | pmid = 24121554 | doi = 10.1038/nchembio.1362 | pmc = 4034760 }}</ref><ref>{{cite journal | vauthors = Huang SS, Koder RL, Lewis M, Wand AJ, Dutton PL | title = The HP-1 maquette: from an apoprotein structure to a structured hemoprotein designed to promote redox-coupled proton exchange | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 15 | pages = 5536–5541 | date = April 2004 | pmid = 15056758 | doi = 10.1073/pnas.0306676101 | pmc = 397418 | doi-access = free }}</ref>
* Peroxidases<ref>{{cite journal | vauthors = Faiella M, Maglio O, Nastri F, Lombardi A, Lista L, Hagen WR, Pavone V | title = De novo design, synthesis and characterisation of MP3, a new catalytic four-helix bundle hemeprotein | journal = Chemistry: A European Journal | volume = 18 | issue = 50 | pages = 15960–15971 | date = December 2012 | pmid = 23150230 | doi = 10.1002/chem.201201404 }}</ref><ref>{{cite journal | vauthors = Cherry JR, Lamsa MH, Schneider P, Vind J, Svendsen A, Jones A, Pedersen AH | title = Directed evolution of a fungal peroxidase | journal = Nature Biotechnology | volume = 17 | issue = 4 | pages = 379–384 | date = April 1999 | pmid = 10207888 | doi = 10.1038/7939 | s2cid = 41233353 }}</ref>
* Electron transport proteins<ref>{{cite journal | vauthors = Anderson JL, Armstrong CT, Kodali G, Lichtenstein BR, Watkins DW, Mancini JA, Boyle AL, Farid TA, Crump MP, Moser CC, Dutton PL | display-authors = 6 | title = Constructing a man-made c-type cytochrome maquette ''in vivo'': electron transfer, oxygen transport and conversion to a photoactive light harvesting maquette | journal = Chemical Science | volume = 5 | issue = 2 | pages = 507–514 | date = February 2014 | pmid = 24634717 | doi = 10.1039/C3SC52019F | pmc = 3952003 }}</ref>
* Oxygen transport proteins<ref>{{cite journal | vauthors = Koder RL, Anderson JL, Solomon LA, Reddy KS, Moser CC, Dutton PL | title = Design and engineering of an O(2) transport protein | journal = Nature | volume = 458 | issue = 7236 | pages = 305–309 | date = March 2009 | pmid = 19295603 | doi = 10.1038/nature07841 | pmc = 3539743 | bibcode = 2009Natur.458..305K }}</ref>
* Photosensitive proteins<ref name=":1" />

Design techniques have matured to such an extent that it is now possible to generate entire libraries of heme binding helical proteins.<ref>{{cite journal | vauthors = Moffet DA, Foley J, Hecht MH | title = Midpoint reduction potentials and heme binding stoichiometries of de novo proteins from designed combinatorial libraries | journal = Biophysical Chemistry | volume = 105 | issue = 2–3 | pages = 231–239 | date = September 2003 | pmid = 14499895 | doi = 10.1016/S0301-4622(03)00072-3 | series = Walter Kauzmann's 85th Birthday | doi-access = free }}</ref>

Recent design attempts have focused on creating all-beta heme binding proteins, whose novel topology is very rare in nature. Such designs include:
* Pincer-1<ref name=":0" />
* [[β-hairpin]] peptides<ref>{{cite journal | vauthors = Mahajan M, Bhattacharjya S | title = β-Hairpin peptides: heme binding, catalysis, and structure in detergent micelles | journal = Angewandte Chemie | volume = 52 | issue = 25 | pages = 6430–6434 | date = June 2013 | pmid = 23640811 | doi = 10.1002/anie.201300241 }}</ref>
* β-sheet miniproteins<ref>{{cite journal | vauthors = D'Souza A, Wu X, Yeow EK, Bhattacharjya S | title = Designed Heme-Cage β-Sheet Miniproteins | journal = Angewandte Chemie | volume = 56 | issue = 21 | pages = 5904–5908 | date = May 2017 | pmid = 28440962 | doi = 10.1002/anie.201702472 }}</ref>
* Multi-stranded β-sheet peptides<ref>{{cite journal | vauthors = D'Souza A, Mahajan M, Bhattacharjya S | title = Designed multi-stranded heme binding β-sheet peptides in membrane | journal = Chemical Science | volume = 7 | issue = 4 | pages = 2563–2571 | date = April 2016 | pmid = 28660027 | pmc = 5477022 | doi = 10.1039/C5SC04108B }}</ref>
Some methodologies attempt to incorporate cofactors into the hemoproteins who typically endure harsh conditions. In order to incorporate a synthetic cofactor, what must first occur is the denaturing of the holoprotein to remove the heme. The apoprotein is then rebuilt with the cofactor.<ref>{{Cite journal |last1=Lemon |first1=Christopher M. |last2=Marletta |first2=Michael A. |date=2021-12-21 |title=Designer Heme Proteins: Achieving Novel Function with Abiological Heme Analogues |journal=Accounts of Chemical Research |language=en |volume=54 |issue=24 |pages=4565–4575 |doi=10.1021/acs.accounts.1c00588 |issn=0001-4842 |pmc=8754152 |pmid=34890183}}</ref>