Chemistry:QTY Code
The QTY Code is a design method to transform membrane proteins that are intrinsically insoluble in water into variants with water solubility, while retaining their structure and function.
Similar structures of amino acids
The QTY Code is based on two key molecular structural facts: 1) all 20 natural amino acids are found in alpha-helices regardless of their chemical properties, although some amino acids have a higher propensity to form an alpha-helix; and, 2) several amino acids share striking structural similarities despite their very different chemical properties. These may be paired as: Glutamine (Q) vs Leucine (L); Threonine (T) vs Valine (V) and Isoleucine (I); and Tyrosine (Y) vs Phenylalanine (F).[1][2]
The QTY Code systematically replaces water-insoluble amino acids (L, V, I and F) with water-soluble amino acids (Q, T and Y) in transmembrane alpha-helices.[3] Thus, its application to membrane proteins changes the water-insoluble form of membrane proteins into water-soluble variants.[3][4] The QTY Code was specifically conceived to render G protein-coupled receptors (GPCRs) into a water-soluble form. Despite substantial transmembrane domain changes, the QTY variants of GPCRs maintain stable structure and ligand binding activities.[3][4][5][6][7]
File:H-bonds of N, Q, S, T, Y.tif
Hydrogen bond interactions between water and the amino acids
The side chain of glutamine (Q) can form 4 hydrogen bonds with 4 water molecules. There are 2 hydrogen donors from nitrogen and 2 hydrogen acceptors for oxygen. The –OH group of threonine (T) and tyrosine (Y) can form 3 hydrogen bonds with 3 water molecules (2 H-acceptors and 1 H-donor).[1] Color code: Green = carbon, red = oxygen, blue = nitrogen, gray = hydrogen, yellow disks = hydrogen bonds.
File:Shuguang QTY illulstration.tif
Three types of alpha-helices and with nearly identical molecular structure
There are 3 types of alpha-helices and with nearly identical molecular structure, namely: a) 1.5Å per amino acid rise, b) 100˚ per amino acid turn, c) 3.6 amino acids and 360˚ per helical turn, and d) 5.4Å per helical turn. The 3 types of alpha-helices are: 1) mostly hydrophobic amino acids including Leucine (L), Isoleucine (I), Valine (V), Phenylalanine (F), Methionine (M) and Alanine (A) that are commonly found as the helical transmembrane segments in membrane proteins; 2) mostly hydrophilic amino acids including Aspartic acid (D), Glutamic acid (E), Glutamine (Q), Lysine (K), Arginine (R), Serine (S), Threonine (T), Tyrosine (Y) that are commonly found on the out layer in water-soluble globular proteins; 3) mixed hydrophobic and hydrophilic amino acids that are partitioned in 2 faces: hydrophobic face and hydrophilic face, in an analogy, like our fingers with front and back. These alpha-helices sometimes attach to surface of membrane lipid bilayer, or partially buried to the hydrophobic core and partially close to the surface of water-soluble globular proteins.[2]
The QTY code
The QTY Code is likely universally applicable and also reversible, namely, Q changes to L, T changes to V and I, and Y changes to F. The QTY Code has been successful in designing many water-soluble variants of chemokine receptors and cytokine receptors. The QTY Code may likely be successfully applied to other water-insoluble aggregated proteins. The QTY Code is robust and straightforward: it is the simplest tool to carry out membrane protein design without sophisticated computer algorithms. Thus, it can be used broadly. The QTY Code has implications for designing additional GPCRs and other membrane proteins including cytokine receptors that are directly involved in cytokine storm syndrome.[3][4][5][6][7]
The QTY Code has also been applied to cytokine receptor water-soluble variants with the aim of combatting the cytokine storm syndrome (also called cytokine release syndrome) suffered by cancer patients receiving CAR-T therapy. This therapeutic application may be equally applicable to severely infected COVID-19 patients, for whom cytokine storms often lead to death.[7]
In 2021, predictions of AlphaFold 2 program proved the validity of QTY code.[8]
References
- ↑ Jump up to: 1.0 1.1 Stryer, Lubert (January 1, 1981). Biochemistry (2 ed.). W.H. Freeman and Company.
- ↑ Jump up to: 2.0 2.1 Branden, Carl Ivar; Tooze, John (January 1, 1999). Introduction to Protein Structure (2 ed.). Garland Science. ISBN 9780815323051.
- ↑ Jump up to: 3.0 3.1 3.2 3.3 Zhang, Shuguang; Tao, Fei; Qing, Rui; Tang, Hongzhi; Skuhersky, Michael; Corin, Karolina; Tegler, Lotta; Wassie, Asmamaw et al. (September 11, 2018). "QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities". PNAS 115 (37): E8652–E8659. doi:10.1073/pnas.1811031115. PMID 30154163.
- ↑ Jump up to: 4.0 4.1 4.2 Qing, Rui; Skuhersky, Michael; Chung, Haeyoon; Badr, Myriam; Schubert, Thomas; Zhang, Shuguang (December 17, 2019). "QTY code designed thermostable and water-soluble chimeric chemokine receptors with tunable ligand affinity". PNAS 116 (51): 25668–25676. doi:10.1073/pnas.1909026116. PMID 31776256.
- ↑ Jump up to: 5.0 5.1 Hao, Shilei; Jin, David; Zhang, Shuguang; Qing, Rui (9 April 2020). "QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands". QRB Discovery 1: e4. doi:10.1017/qrd.2020.4. PMID 34192260.
- ↑ Jump up to: 6.0 6.1 Tegler, Lotta; Corin, Karolina; Pick, Horst; Brookes, Jennifer; Skuhersky, Michael; Vogel, Horst; Zhang, Shuguang (7 December 2020). "The G protein coupled receptor CXCR4 designed by the QTY code becomes more hydrophilic and retains cell signaling activity". Scientific Reports 10 (1): 21371. doi:10.1038/s41598-020-77659-x. PMID 33288780. Bibcode: 2020NatSR..1021371T.
- ↑ Jump up to: 7.0 7.1 7.2 Qing, Rui; Tao, Fei; Chatterjee, Pranam; Yang, Gaojie; Han, Qiuyi; Chung, Haeyoon; Ni, Jun; Suter, Bernhard et al. (18 December 2020). "Non-full-length Water-Soluble CXCR4QTY and CCR5QTY Chemokine Receptors: Implication for Overlooked Truncated but Functional Membrane Receptors". iScience 23 (12): 101670. doi:10.1016/j.isci.2020.101670. PMID 33376963. Bibcode: 2020iSci...23j1670Q.
- ↑ Skuhersky, Michael; Tao, Fei; Qing, Rui; Smorodina, Eva; Jin, David; Zhang, Shuguang (24 November 2021). "Comparing Native Crystal Structures and AlphaFold2 Predicted Water-S". Life 11 (12): 1285. doi:10.3390/life11121285. PMID 34947816.
Further reading
- Hung, Chien-Lun; Kuo, Yun-Hsuan; Lee, Su Wei; Chiang, Yun-Wei (2021). "Protein Stability Depends Critically on the Surface Hydrogen-Bonding Network: A Case Study of Bid Protein". The Journal of Physical Chemistry B 125 (30): 8373–8382. doi:10.1021/acs.jpcb.1c03245. PMID 34314184.
- Zayni, Sonja; Damiati, Samar; Moreno-Flores, Susana; Amman, Fabian; Hofacker, Ivo; Jin, David; Ehmoser, Eva-Kathrin (2021). "Enhancing the Cell-Free Expression of Native Membrane Proteins by in Silico Optimization of the Coding Sequence—An Experimental Study of the Human Voltage-Dependent Anion Channel". Membranes 11 (10): 741. doi:10.3390/membranes11100741. PMID 34677509.
- Root-Bernstein, Robert; Churchill, Beth (2021). "Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities". Life 11 (11): 1217. doi:10.3390/life11111217. PMID 34833093.
- Vorobieva, Anastassia Andreevna (2021). "Principles and Methods in Computational Membrane Protein Design". Journal of Molecular Biology 433 (20): 167154. doi:10.1016/j.jmb.2021.167154. PMID 34271008.
- Martin, Joseph; Sawyer, Abigail (2019). "Elucidating the structure of membrane proteins". BioTechniques 66 (4): 167–170. doi:10.2144/btn-2019-0030. PMID 30987442.
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