Fundamentals of Biochemistry - Filippovich, Y. B. 1999

Quantum Mechanical Aspects of Biochemistry

When examining the Structure and properties of various compounds, as well as certain biochemical processes in the preceding chapters, an attempt was made to apply quantum-mechanical concepts to explain A number of phenomena and regularities. In particular, this approach was used to describe the peptide bond (the dependence of its properties on electron delocalization and conjugation) and the Introduction/11.html">Secondary structure of the protein (THE CONTRIBUTION OF п-electrons to maintaining the a-helical conformation) (see Ch. II), the MECHANISM OF ACTION of pyridoxal Enzymes (electron density displacement in the enzyme-substrate complex — see Ch. III), The Nature of the cis-trans isomeric transformations of retinal (the dependence of this phenomenon on bond order values in the conjugated system), the structure and properties of thiamine pyrophosphate (the cause of increased electron density at the 2nd carbon atom of the thiazole ring), and the enhanced reactivity of isoalloxazine at the 1st and 10th positions (where free valence indices are maximal) (see Ch. IV). It was also applied when discussing The Essence of life, studying the nature of high-energy bonds (instability of the electron conjugation system) (see Ch. V), the structure and properties of pyrimidine and purine bases (the relationship between bond order and addition reactions), stacking interactions in DNA molecules (their alteration upon contact of Water molecules with proton-donor and proton-acceptor centers of nitrogenous bases) (see Ch. VI), The Mechanism of molecular oxygen activation during Biological Oxidation (see Ch. X), and in several other cases.

As can be seen from this enumeration, this guide utilizes only some of the most elementary concepts of quantum biochemistry, which emerged as an independent scientific discipline in the early 1960s. It arose at the intersection of quantum chemistry and molecular biology, and more broadly, at the border between physics and biology, gradually evolving into an exciting and promising new science: physical-chemical biology.

The logic and rationale behind the emergence and development of quantum biochemistry lie in the fact that, moving beyond elementary notions of elemental composition, arrangement order, and spatial localization of atoms in organic molecules (which are, naturally, of biological significance), it enables a transition—via quantum-mechanical calculations—to data on electron density distribution and electron cloud mobility, as well as energy characteristics that reflect molecular stability and their capacity to donate and accept electrons, ultimately revealing their reactivity and the relationship between structure and biological function.

Quantum-mechanical calculations provide fairly clear insights into the energy indices of molecules (electron delocalization energy, highest occupied molecular orbital energy, lowest unoccupied molecular orbital energy, excitation energy), as well as their structural indices (atomic electron charges, bond order, free valence index).

Knowledge of electron delocalization energy levels (the difference between the observed energy of a molecule and the energy calculated based on its canonical structural formula) is essential for a deeper understanding of the mechanism of action of Coenzymes and other biologically active compounds featuring a system of conjugated double bonds. Furthermore, electron delocalization energy values are important for assessing the stability of Hydrogen Bonds between complementary purine and pyrimidine bases, and they are crucial when addressing equilibria in various tautomeric transformations of Monosaccharides, keto acids, nitrogenous bases, and the like. Data on the energies of the highest occupied and lowest unoccupied orbitals are directly correlated with the electron-donating and electron-accepting properties of molecules, respectively, and are used to characterize cellular oxidoreductase systems. Information on excitation energy—that is, the difference in an electron's energy before and after transition to a new Orbit—has been repeatedly discussed in connection with the semiconductor Properties of Proteins and NUCLEIC ACIDS.

As for structural indices of molecules, they are most frequently considered when examining the relationship between the Structure and function of Organic compounds. Atomic electron charges, which characterize the probability of an electron being located near a given atom across all its occupied orbitals, are distributed in a specific manner, for instance, in readily hydrolyzable substrates, including high-energy ones (see data on electron-deficient bonds in ATP molecules — Ch. V). Bond order, which characterizes the relative proximity of a given bond to a standard single or double bond, helps to understand the reactivity of specific molecular regions not only in Pyrimidines and Purines, but also in more complex compounds (a classic example here is the identification of the highly reactive so-called K-region in the molecules of carcinogenic aromatic Hydrocarbons). Free valence indices of atoms (as an indicator of residual, unfulfilled valence at a given atom) point to the most reactive centers in a molecule where free radicals or hydrogen atoms may attach (see The structure of the isoalloxazine ring in the vitamin B₂ molecule).

An examination of the Current state of quantum-mechanical approaches to analyzing biochemical processes shows that the most fruitful results have been obtained in interpreting the mechanisms of various enzymatic reactions (aminotransferase, oxidoreductase, lyase, etc.), the nature of high-energy bonds, the carcinogenicity of aromatic hydrocarbons, the Structural and functional features of nucleic acids, and the relationship between Molecular structure and pharmacological effect. For example, quantum-chemical calculations of electronic transition energies for various Ionic Forms of pyridoxal-5-phosphate, pyridoxamine-5-phosphate, and oxime-pyridoxal-5-phosphate formed during the aminotransferase reaction have yielded good agreement with spectroscopic data, helping to elucidate the nature of intermediate coenzyme-substrate complexes in this reaction. Based on the hypothesis that the N—O—O atomic triangle within antitumor anthraquinone derivatives is responsible for this biological activity, a potent new cancerostatic agent was synthesized: 1,4-dihydroxy-5,8-bis-2-(hydroxyethyl)aminoethylamino-9,10-anthracenedione. This further underscored the fruitfulness of applying quantum biochemistry Methods to understand the mechanism of biological activity of carcinogenic and anticancer substances, a path initiated by the classical work of A. Pullman and B. Pullman concerning the ability of carcinogenic hydrocarbons to interact with The Cell via the K-region:

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To some extent, quantum biochemical data have proved useful in explaining The properties of PROTEINS AND Peptides, as well as porphyrin compounds.

At the same time, one must realistically recognize that quantum biochemistry is at the very beginning of its journey. Significant difficulties exist in quantum-chemical calculations of the electronic structure of moderately complex molecules, let alone full DNA, RNA, and protein molecules—nature's most vital Biopolymers. Its calculations are apparently valid only for fixed molecular structures, yet they do not yet account for the multiple conformational states of macromolecules, which inevitably affect electron density distributions. An unresolved issue remains the distribution of charges in the studied compound depending on the Nature of the solvent and the interaction of its molecules with the atomic groups of the substance under investigation—in other words, the question of the accuracy of electronic characteristics for a substance within the biological fluid where biochemical reactions actually take place.

An even more challenging, yet undoubtedly central, task of quantum biochemistry is The Study of intermolecular interactions, along with the estimation and comparison of energy values in emerging complexes, where the molecular orbital method is clearly insufficient due to the impossibility of accounting for electron correlation. Therefore, researchers currently place their hopes in quantum-statistical approaches, which essentially consider the statistics of molecules rather than electrons. At the same time, the LCAO (Linear Combination of Atomic Orbitals) method has yielded quite satisfactory results in "quantum pharmacology" (for example, predicting new neuroleptics). Finally, all constructs of modern quantum biochemistry are developed without taking into account that molecular interactions in living systems occur at a higher, qualitatively new level of Organization. Examples of this include the pictographic mode of Molecular recognition during reception (pattern recognition rather than specific atomic or electronic structures), as well as the principles embedded in a new scientific direction: topobiology—the study of biological interactions determined by the spatial arrangement of biological structures, which provides a key to understanding the most complex problems of morphogenesis.

Also worthy of mention are the emerging trends that view the Spatial Organization of certain biological structures, such as the protein Cytoskeleton, as a computer system capable of continuous information Processing and command generation to ensure normal cell vitality. In this regard, the core methodological principle of quantum biochemistry—reducing the phenomena of life to the "self-realization of the potential capabilities of atomic electronic states"—is hardly justified.