Form and Function in Biological Macromolecules: Kinetic Stability is Key, with Oblique Roles for Intramolecularity and Hydrophobicity in Enzyme Catalysis

Sosale Chandrasekhar *

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.

*Author to whom correspondence should be addressed.


Abstract

Certain structure-reactivity aspects of biological macromolecules, with particular emphasis on protein folding and enzyme catalysis, are discussed herein. Furthermore, the role played by the hydrophobic effect and intramolecularity in enzymic reactivity are evaluated afresh, with new insights of much importance in chemical biology.

Thus, the sum of the energies of the hydrogen bonds constituting the tertiary structures of proteins, determines the overall Gibbs energy of activation for loss of conformational integrity. As protein molecules of even modest size consist of a relatively large number of intramolecular hydrogen bonding interactions, the activation barrier to even partial unfolding of the α-helices and β-sheets forming the tertiary structure would be prohibitively high under normal conditions.

The resulting kinetic stability conserves the natural conformation of a protein molecule established at the ribosomal site of synthesis, carrying the molecule through the thick-and-thin of a range of metabolic pathways during its ‘journey of life’. However, protein molecules also acquire flexibility via ‘strain delocalization’ (Ramachandran plots being relevant), thus enabling stabilization of multiple transition states along a pathway (particularly in case of covalent enzyme-substrate complexes).

Two mechanistic features of enzyme catalysis that have been exhaustively studied are intramolecularity and the hydrophobic effect. Although intramolecularity has for long been touted as the origin of enzymic reactivity, this can be challenged on fundamental physical-organic grounds. Intriguingly, however, the collapse of the classical Michaelis-Menten mechanism for enzyme catalysis leads to a reconsideration of the role of intramolecularity, although not as hitherto envisaged. Thus, a majority of enzymes apparently form covalent enzyme-substrate complexes—possibly also exergonically—so the subsequent reactions at the active site may well benefit from the traditional propinquity effect: The critical caveat would be the highly exergonic formation of final products.

It is argued that the hydrophobic effect—although intuitively reasonable—is difficult to pin down quantitatively, model systems (including micelles) leading to inconsistent and debatable results. However, the hydrophobic effect likely contributes to enzymic reactivity along with charge-relay via the proteinic backbone.

Keywords: Hydrogen bonding, Michaelis-Menten, micelles, propinquity effect, protein folding, Ramachandran plots


How to Cite

Chandrasekhar, Sosale. 2022. “Form and Function in Biological Macromolecules: Kinetic Stability Is Key, With Oblique Roles for Intramolecularity and Hydrophobicity in Enzyme Catalysis”. International Journal of Biochemistry Research & Review 31 (9):17-26. https://doi.org/10.9734/ijbcrr/2022/v31i9778.

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References

Agarwal PK. A biophysical perspective on enzyme catalysis. Biochemistry. 2019; 58(6):438–449.

DOI: 10.1021/acs.biochem.8b01004

Kirby AJ, Hollfelder F. From enzyme models to model enzymes. Cambridge (UK): Royal Society of Chemistry; 2009.

Chandrasekhar S. The origins of enzyme catalysis and reactivity: Further assessments. Asian Journal of Chemical Sciences. 2021;9(3):38-47.

DOI: 10.9734/AJOCS/2021/v9i319075

Chandrasekhar S. Understanding enzymic reactivity – new directions and approaches. Asian Journal of Research in Biochemistry. 2020;7(2):1-13.

DOI: 10.9734/ajrb/2020/v7i230133

Zhang X, Houk KN. Why enzymes are proficient catalysts: Beyond the Pauling paradigm. Acc Chem Res. 2005:38(5): 379-385.

DOI: 10.1021/ar040257s

Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. Molecular Biology of the Gene. 7th Ed. Boston: Pearson; 2013.

Chandrasekhar S. Intramolecularity and enzyme modelling: A critique. Res Chem Intermed. 2003;29(1):107-123.

DOI: 10.1163/156856703321328451

Chandrasekhar S. The hydrophobic effect in chemistry, biology and medicine: An update. Asian Journal of Chemical Sciences. 2021;9(4):22-36.

DOI: 10.9734/AJOCS/2021/v9i419078

Atkins P, de Paula J. Atkins’ physical chemistry. 8th Ed. New York: W. H. Freeman; 2006.

Silverman RB. The organic chemistry of enzyme-catalyzed reactions. San Diego: Academic Press; 2002.

Fersht A. Structure and mechanism in protein science. 2nd Ed. Cambridge (UK): Kaissa Publications; 2017.

Chandrasekhar S. The Gibbs energy–potential energy conundrum and chemical reactivity: Implications for catalysis and enzyme action. Asian Journal of Chemical Sciences. 2021;9(4):1-7.

DOI: 10.9734/AJOCS/2021/v9i41907

Dill KA, MacCallum JL. The protein folding problem, 50 years on. Science. 2012; 338(6110):1042-1046.

DOI: 10.1126/science.1219021

Kuriyan J, Konforti B, Wemmer D. The molecules of life: Physical and chemical principles. New York: Garland Science; 2013.

Kessel A, Ben-Tal N. Introduction to proteins structure, function and motion. 2nd Ed. Boca Raton: CRC Press; 2018.

Buxbaum E. Fundamentals of protein structure and function. New York: Springer Science; 2017.

Koltzenburg S, Maskos M, Nuyken O, Hughes K. Polymer chemistry. Berlin-Heidelberg: Springer-Verlag; 2017.

Rosenberg AA, Marx A, Bronstein AM. Codon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon. Nat Commun. 2022;13:2815.

DOI: 10.1038/s41467-022-30390-9

Nelson DL, Cox MM. Lehninger principles of biochemistry. 7th Ed. New York: Freeman; 2017.

Anslyn EV, Dougherty DA. Modern physical organic chemistry. Sausalito CA: University Science Books; 2006.

Olivares AO, Baker TA, Sauer RT. Mechanical protein unfolding and degradation. Annu Rev Physiol. 2018;80: 413-429

DOI:10.1146/annurev-physiol-021317-121303