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Ultimate Molecular Theory of Sweet Taste Huazhong He, PHD ( [email protected] ) Molecular Recognition Organization https://orcid.org/0000-0001-8881-9325 Research Article Keywords: Sweet Receptor Protein Helix, Helix Tightening-Comeback Torsion-Spring-Like Oscillation, DH- B, Hydrogen Bond, Multiple Binding Sites, Potency Versus Intensity Posted Date: January 29th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-141448/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

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Page 1: Ultimate Molecular Theory of Sweet Taste - Research Square

Ultimate Molecular Theory of Sweet TasteHuazhong He, PHD  ( [email protected] )

Molecular Recognition Organization https://orcid.org/0000-0001-8881-9325

Research Article

Keywords: Sweet Receptor Protein Helix, Helix Tightening-Comeback Torsion-Spring-Like Oscillation, DH-B, Hydrogen Bond, Multiple Binding Sites, Potency Versus Intensity

Posted Date: January 29th, 2021

DOI: https://doi.org/10.21203/rs.3.rs-141448/v2

License: This work is licensed under a Creative Commons Attribution 4.0 International License.  Read Full License

Page 2: Ultimate Molecular Theory of Sweet Taste - Research Square

Ultimate Molecular Theory of Sweet Taste

Huazhong He, Ph. D

Molecular Recognition Organization, Elwood Rd., Delmar, NY 12054

[email protected]

ABSTRACT

More than thirty years ago, I proposed a theory about sweet and bitter molecules’ recognition by protein helical structures. Unfortunately the papers could not go to public platform until now. The sweet and bitter taste theory is updated and presented in separated papers1,2. The sweet taste theory conveys that sweet molecules are recognized by receptor protein helical structures and the recognition process is a dynamic action, in which the sweet receptor protein helix has a torsion-spring-like oscillation between helical structures of 3.6 and 3 amino acids per turn. To help this kind of oscillation, there are two kinds of hydrogen donor and hydrogen acceptor DH-B entities for both receptor and sweet molecules: H-bond or non-H-bond. The distances between DH and B could be up to ~ 8.5 Å. The receptor H-bond type DH-B entities are the NH-O pairs forming H-bonds in protein helices; the receptor non-H-bond type DH-B entities are the ones from two pairs of NH-Os forming H-bonds which are about one turn away. To facilitate this kind of movement, the interaction of DH-Bs of a sweet molecule with those of sweet receptor, through a pair of complementary hydrogen bonds, must have hydrogen bond complementarities, which means H-bond type of ligands’ DH-Bs reacts on non-H-bond type of receptor’s O-NHs, and vice versa. As the oscillation may have different extent, it translates to sweet intensity. As recognition sites are only associated with a small fraction – helix structure of whole sweet receptor, multiple binding sites or multiple receptors are well expected. KEY WORDS: Sweet Receptor Protein Helix, Helix Tightening-Comeback Torsion-Spring-Like Oscillation, DH-B, Hydrogen Bond, Multiple Binding Sites, Potency Versus Intensity

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receptor, the hydrophobicity of sweetener molecule is an important trait to increase sweetness potency as a whole. The identification of multiple locations about sweeteners binding undoubtedly is a strong indirect support about helices’ recognition about sweeteners. With the guidance of this theory, it is unprecedented to be able to explain sweetness-structure relationships of achiral & chiral molecules, two types of DH-Bs/NH-Os & their distance information, potency vs intensity, multiple binding sites etc.

ACKNOWLEDGEMENT

I am grateful to Dr. Fengxia Deng for her decades-long encouragement and support for completing this research. I would like to thank Mr. Charlie He for his help in organizing data. I would also like to thank the late Professor Guangzhi Zeng (Kuangchi Tseng) for leading me into this fascinating area.

CONFLICT OF INTEREST

The author declares no conflicts of interest with the contents of this article.

FUNDING

There is no funding for this research.

REFERENCES

1 He, Huazhong: Deciphering Aspartyl Peptide Sweeteners Using the Ultimate Molecular Theory of Sweet Taste. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.13488177 (2021).

2 He, Huazhong: Ultimate Molecular Theory of Bitter Taste. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.13622423 (2021).

3 Zeng, G. & Wei, S. Molecular recognition of Gustation (Science Press (China) 1984).

4 Moncrieff, R. W. The Chemical Senses. (CRC Press, 1967). 5 Vauquelin, L.-N. "De l'Aiguemarine, ou Béril; et découverie d'une terre

nouvelle dans cette pierre" [Aquamarine or beryl; and discovery of a new earth in this stone]. Annales de Chimie 26, 169 (1798).

6 Hernberg, S. Lead Poisoning in a Historical Perspective. American Journal of Industrial Medicine 38, 244-254 (2000).

7 Cohn, G. Die Organischen Geschmacksstoffe. (Fritz Siemenroth: Berlin, 1914).

8 Oertly, E. & Myers, R. G. A New Theory Relating Constitution to Taste. [Preliminary Paper.] Simple Relations Between The Constitution of Aliphatic Compounds and Their Sweet Taste. Journal of the American Chemical Society 41, 855-867, doi:10.1021/ja02227a001 (1919).

9 Shallenberger, R. S. & Acree, T. E. Molecular Theory of Sweet Taste. Nature 216, 480-482 (1967).

Page 24: Ultimate Molecular Theory of Sweet Taste - Research Square

22

10 Kier, L. B. A molecular theory of sweet taste. J Pharm Sci 61, 1394-1397 (1972).

11 Gries, H. et al. Trihalogenated benzamides — a new class of artificial sweeteners. Zeitschrift für Lebensmittel-Untersuchung und Forschung 176, 376-378, doi:10.1007/bf01057731 (1983).

12 Belitz, H.-D., Rohse, H., Stempfl, W. & Gries, H. Trihalogenated benzamides: structure taste relationships. Zeitschrift für Lebensmittel-Untersuchung und Forschung 190, 319-324, doi:10.1007/bf01184500 (1990).

13 Zeng, G. Natural Carbohydrate Sweeteners and Synthetic Analogues. Huaxue Tongbao 11, 18-23 (1989).

14 Nofre, C. & Tinti, J.-M. Sweetness reception in man: the multipoint attachment theory. Food chemistry 56, 263-274, doi:http://dx.doi.org/10.1016/0308-8146(96)00023-4 (1996).

15 Nelson, G. et al. Mammalian Sweet Taste Receptors. Cell 106, 381-390, doi:10.1016/S0092-8674(01)00451-2 (2001).

16 Bachmanov, A. A. et al. Positional cloning of the mouse saccharin preference (Sac) locus. Chem Senses 26, 925-933 (2001).

17 Kitagawa, M., Kusakabe, Y., Miura, H., Ninomiya, Y. & Hino, A. Molecular genetic identification of a candidate receptor gene for sweet taste. Biochem Biophys Res Commun 283, 236-242, doi:10.1006/bbrc.2001.4760 (2001).

18 Li, X., Inoue, M., Reed, D. R., Huque, T., Puchalski, R. B., Tordoff, M. G., Ninomiya, Y., Beauchamp, G. K., Bachmanov, A. A. High-resolution genetic mapping of the saccharin preference locus (Sac) and the putative sweet taste receptor (T1R1) gene (Gpr70) to mouse distal Chromosome 4. Mamm Genome 12, 13-16 (2001).

19 Max, M. et al. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet 28, 58-63, doi:10.1038/88270 (2001).

20 Montmayeur, J. P., Liberles, S. D., Matsunami, H. & Buck, L. B. A candidate taste receptor gene near a sweet taste locus. Nat Neurosci 4, 492-498, doi:10.1038/87440 (2001).

21 Sainz, E., Korley, J. N., Battey, J. F. & Sullivan, S. L. Identification of a novel member of the T1R family of putative taste receptors. J Neurochem 77, 896-903 (2001).

22 Pettersen, E. F., Goddard, Thomas D., Huang, Conrad C., Couch, Gregory S., Greenblatt, Daniel M., Meng, Elaine C., Ferrin, Thomas E. UCSF Chimera—A visualization system for exploratory research and analysis. Journal of Computational Chemistry 25, 1605-1612, doi:10.1002/jcc.20084 (2004).

23 Trott, O. & Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 31, 455-461, doi:10.1002/jcc.21334 (2010).

Page 25: Ultimate Molecular Theory of Sweet Taste - Research Square

23

24 Sanner, M. F. Python: a programming language for software integration and development. J Mol Graph Model 17, 57-61 (1999).

25 Muspratt, J. S. & Hofmann, A. W. Ueber das Nitranilin, ein neues Zersetzungsproduct des Dinitrobenzols. Justus Liebigs Annalen der Chemie 57, 201-224, doi:10.1002/jlac.18460570208 (1846).

26 Blanksma, J. J. & van der Weyden, P. W. M. Relationship between taste and structure in some derivatives of meta-nitraniline. Recueil des Travaux Chimiques des Pays-Bas 59, 629-632, doi:10.1002/recl.19400590705 (1940).

27 Blanksma, J. J. & Hoegen, D. The sweet taste of 4-nitro-2-aminotoluene, 4-nitro-2-aminobenzoic acid and 2-nitro-4-aminobenzoic acid. Recueil des Travaux Chimiques des Pays-Bas 65, 333-337, doi:10.1002/recl.19460650504 (1946).

28 Blanksma, J. J., van den Broek, W. J. & Hoegen, D. On the sweet taste of the 1-halogeno-2-amino-4-nitrobenzenes. Recueil des Travaux Chimiques des Pays-Bas 65, 329-332, doi:10.1002/recl.19460650503 (1946).

29 Zeng, Guangzhi (Tseng, Kuangchih) Structural chemistry of sweet molecules and synthetic sweeteners. Chinese Journal of Applied Chemistry 7, 11-26 (1990).

30 Kawai, M., Sekine-Hayakawa, Y., Okiyama, A. & Ninomiya, Y. Gustatory sensation of (L)- and (D)-amino acids in humans. Amino Acids 43, 2349-2358, doi:10.1007/s00726-012-1315-x (2012).

31 Nofre, C., Sabadie, J. & Bal, D. Sweetening properties of L-alanine tert-butyl ester. Naturwissenschaften 61, 404-405 (1974).

32 Jeffrey, G. A. & Maluszynska, H. A survey of hydrogen bond geometries in the crystal structures of amino acids. International journal of biological macromolecules 4, 173-185, doi:http://dx.doi.org/10.1016/0141-8130(82)90048-4 (1982).

33 Birch, G. G. Sweetness and sweeteners. Endeavour 11, 21-24, doi:http://dx.doi.org/10.1016/0160-9327(87)90165-7 (1987).

34 Ariyoshi, Y., Yasuda, N. & Yamatani, T. The structure-taste relationships of the dipeptide esters composed of L-aspartic acid and β-hydroxy amino acids. Bulletin of the Chemical Society of Japan 47, 326-330 (1974).

35 Janusz, J. M. et al. High potency dipeptide sweeteners. 1. L-aspartyl-D-phenylglycine esters. J Med Chem 33, 1052-1061 (1990).

36 Muller, G. W., Walters, D. E. & DuBois, G. E. N,N'-disubstituted guanidine high-potency sweeteners. J Med Chem 35, 740-743 (1992).

37 Kawai, M., Chorev, M., Marin-Rose, J. & Goodman, M. Peptide sweeteners. 4. Hydroxy and methoxy substitution of the aromatic ring in L-aspartyl-L-phenylalanine methyl ester. Structure-taste relationships. J Med Chem 23, 420-424 (1980).

38 Acton, E. M., Leaffer, M. A., Oliver, S. M. & Stone, H. Structure-taste relations in oximes related to perillartine. Journal of agricultural and food chemistry 18, 1061-1068 (1970).

39 Kinghorn, A. D. & Soejarto, D. D. Intensely sweet compounds of natural origin. Med Res Rev 9, 91-115 (1989).

Page 26: Ultimate Molecular Theory of Sweet Taste - Research Square

24

40 Nofre, C., Tinti, J. M. & Chatzopoulos-Ouar, F. Agents édulcorants dérivés des acides n-phénylguanidinoacétique et n-phényléthanamidinoacétique et compositions contenant de tels agents édulcorants. EP 0241395A2 (1987).

41 Stone, H. & Oliver, S. M. Measurement of the Relative Sweetness of Selected Sweeteners and Sweetener Mixtures. Journal of food science 34, 215-222, doi:10.1111/j.1365-2621.1969.tb00922.x (1969).

42 Moskowitz, H. R. Sweetness and intensity of artificial sweeteners. Perception & psychophysics 8, 40-42, doi:10.3758/bf03208930 (1970).

43 Fry, J. C., Yurttas, N., Biermann, K. L., Lindley, M. G. & Goulson, M. J. The sweetness concentration-response of r,r-monatin, a naturally occurring high-potency sweetener. J Food Sci 77, S362-364, doi:10.1111/j.1750-3841.2012.02885.x (2012).

44 Hoppe, K. & Gaßmann, B. Bestimmung der Mißgeschmacksschwellen von Saccharin, Cyclamat, Acesulfam und Aspartam. Food / Nahrung 29, 417-420, doi:10.1002/food.19850290431 (1985).

45 Schiffman, S. S., Lindley, M. G., Clark, T. B. & Makino, C. Molecular mechanism of sweet taste: relationship of hydrogen bonding to taste sensitivity for both young and elderly. Neurobiol Aging 2, 173-185 (1981).

46 DuBois, G. E. et al. in Sweeteners Vol. 450 ACS Symposium Series Ch. 20, 261-276 (American Chemical Society, 1991).

47 DuBois, G. E. Molecular mechanism of sweetness sensation. Physiol Behav 164, 453-463, doi:10.1016/j.physbeh.2016.03.015 (2016).

48 Nie, Y., Vigues, S., Hobbs, J. R., Conn, G. L. & Munger, S. D. Distinct contributions of T1R2 and T1R3 taste receptor subunits to the detection of sweet stimuli. Curr Biol 15, 1948-1952, doi:10.1016/j.cub.2005.09.037 (2005).

49 Xu, H., Staszewski, L., Tang, H., Adler, E., Zoller, M., Li, X. Different functional roles of T1R subunits in the heteromeric taste receptors. Proc Natl Acad Sci U S A 101, 14258-14263, doi:10.1073/pnas.0404384101 (2004).

50 Jiang, P. et al. Identification of the cyclamate interaction site within the transmembrane domain of the human sweet taste receptor subunit T1R3. J Biol Chem 280, 34296-34305, doi:10.1074/jbc.M505255200 (2005).

51 Winnig, M., Bufe, B., Kratochwil, N. A., Slack, J. P. & Meyerhof, W. The binding site for neohesperidin dihydrochalcone at the human sweet taste receptor. BMC Struct Biol 7, 66, doi:10.1186/1472-6807-7-66 (2007).

52 Masuda, K. et al. Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. PLoS One 7, e35380, doi:10.1371/journal.pone.0035380 (2012).

53 Maillet, E. L. et al. Characterization of the Binding Site of Aspartame in the Human Sweet Taste Receptor. Chem Senses 40, 577-586, doi:10.1093/chemse/bjv045 (2015).

54 Koizumi, A. et al. Taste-modifying sweet protein, neoculin, is received at human T1R3 amino terminal domain. Biochem Biophys Res Commun 358, 585-589, doi:10.1016/j.bbrc.2007.04.171 (2007).

Page 27: Ultimate Molecular Theory of Sweet Taste - Research Square

25

55 Jiang, P. et al. The cysteine-rich region of T1R3 determines responses to intensely sweet proteins. J Biol Chem 279, 45068-45075, doi:10.1074/jbc.M406779200 (2004).

56 Masuda, T. et al. Five amino acid residues in cysteine-rich domain of human T1R3 were involved in the response for sweet-tasting protein, thaumatin. Biochimie 95, 1502-1505, doi:10.1016/j.biochi.2013.01.010 (2013).

57 Zhang, F. et al. Molecular mechanism for the umami taste synergism. Proceedings of the National Academy of Sciences 105, 20930-20934, doi:10.1073/pnas.0810174106 (2008).

58 Cai, C. et al. Characterization of the Sweet Taste Receptor Tas1r2 from an Old World Monkey Species Rhesus Monkey and Species-Dependent Activation of the Monomeric Receptor by an Intense Sweetener Perillartine. PLoS One 11, e0160079, doi:10.1371/journal.pone.0160079 (2016).

59 Slack, J. P. Use of a T1R2 nucleic acid sequence to identify tastants. US8124360 (2012).

60 Servant, G. & Servant, N. Screening assays to identify compounds which modulate T1R associated taste modalities which eliminate false positives. US9804157 (2017).

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Figures

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Figure 12

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