Peptide Self-Regulation of Living Systems (Facts and Hypotheses) - Shataeva L. K. 2003

Interaction of Peptides with Cell Nucleus Chromatin
Component Composition and Structure of Chromatin

The Introduction/5.html">Eukaryotic Cell nucleus is the largest intracellular Structure. Its contents are enclosed within a nuclear envelope consisting of two lipid bilayer membranes: an inner and an outer one. The distance between them is 20–30 nm, forming the so-called perinuclear space. The nuclear envelope features fixed, through-going pores (nucleopores) that connect the interior of The Nucleus with the Cytoplasm. In the region of the nucleopores, the outer and inner bilayer membranes of the nuclear envelope merge. The walls of the nucleopores are organized by specific Polypeptides known as nucleoporins. The diameter of the nucleopores is 50–80 nm, and their surface area accounts for approximately 10% of the entire surface of the nuclear envelope (Kagawa, 1985). Proteins enter the nucleus and ribonucleoprotein complexes exit it through these pores. Ribonucleic acid itself does not leave the nucleus on its own.

The inner surface of the nuclear membrane is lined with a fibrous layer of the protein lamin, which contains an ordered lattice of microtubules connecting the nucleoplasm to the inner nuclear membrane.

The interior of the Cell Nucleus is filled with Chromatin—a network of double-helical deoxyribonucleic acid chains associated with Nuclear Proteins that regulate the core processes within The Cell nucleus: METABOLISM/36.html">DNA Replication, the repair of its damaged regions, and the Transcription of Genetic information from DNA to Messenger RNA. The weight ratio of nuclear proteins to DNA in chromatin is approximately 1:1.

The main component of chromatin—high-molecular-weight DNA—is a rigid-chain polyampholyte-type macromolecule whose monomeric units are linked by phosphodiester bonds. Chromatin DNA is characterized by a molecular weight ranging from 20 kDa to 40 GDa. DNA Synthesis (replication) occurs through The addition of a nucleotide 5'-phosphate group to the 3'-hydroxyl group of the preceding deoxyribonucleotide. Thus, a DNA chain, unless circular, has a vector orientation from the 5'-end to the 3'-end (base sequences are written accordingly); the —PO(OH)₂ group is located at the 5'-end, and a hydroxyl group is at the 3'-end.

The structure of a DNA chain can be represented by the following scheme:

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where R represents deoxyribose residues, and A, C, G, and T stand for the nucleic bases adenine, cytosine, guanine, and thymine, respectively (Saenger, 1987).

In the DNA Double helices of each Organism species, The sequence of complementary Base Pairs A—T and G—C is preserved, such that one strand, termed the coding (sense) strand, is paired with its counterpart, the non-coding strand. Furthermore, upon forming a right-handed double helix, the two DNA strands exhibit mutually opposite orientations (Van Holde, 1988).

In the early 1950s, i.e., during the Cytology/cytology/16.html">Early stages of studying the DNA double helix, it was assumed that its geometric structure was regular and that adjacent nucleotide pairs were rotated relative to each other by 36°, meaning there were 10 base pairs per full turn of the helix. More precise crystallography of DNA with a defined base sequence revealed that each sequence possesses a characteristic irregularity—the tilts of the base pairs relative to one another are not constant, which leads to local bends in the helix. A single turn of the DNA double helix has a length of approximately 3.4 nm. These are averaged values for a heterogeneous mixture of DNA. Generally speaking, the DNA double helix should not be viewed as a uniform rod. Its structure exhibits systematic modulations dependent on The nucleotide sequence, which are important in nucleic-acid–peptide recognition (see Section 3.2). This recognition may involve A change in the secondary helical structure of DNA, resulting in The formation of loops, cruciform structures, and knots (Arnott et al., 1983).

The phosphorylated carbohydrate portion of DNA performs structural Functions and facilitates conformational rearrangements of the macromolecule, whereas the linear sequence of purine and pyrimidine bases along the DNA chain contains and preserves specific genetic information. The surface of the DNA double helix features Major and minor grooves, which run along the macromolecule between the two strands of its phosphodiester bonds.

In some cases, random chemical modification of nucleotide bases or their excision from the DNA chain can occur. In particular, cytosine units are the most vulnerable to random modification. Fig. 11 illustrates Examples of the spontaneous Hydrolysis of cytosine and its modification by DNA methyltransferase. Moreover, the formation of A number of non-canonical DNA structures (H-forms)—to which a specific role in regulating genome function is attributed—depends on cytosine protonation. It has been shown that this process is influenced by the existence of a local region of lower pH in the immediate vicinity of the DNA chain under physiological conditions (Ivanova et al., 1998).

To protect genetic information from random damage, an enzyme system operates within chromatin to restore The base sequence of a damaged DNA chain in accordance with the sequence of the complementary (undamaged) chain.

Due to the absence of the 2'-hydroxyl group in deoxyribose, the phosphodiester bond of DNA is significantly more resistant to alkaline hydrolysis than analogous bonds in Ribonucleic Acids. The lower stability of RNA chains is combined with a higher regulatory activity of its monomers. Adenosine (adenine riboside) and guanosine (guanine riboside) are regulatory molecules and are widespread in all cell types. Adenosine is a potent regulator of physiological signal transmission in the central and peripheral nervous systems, the Cells of which contain a specific receptor. It can inhibit or stimulate the release of several Neurotransmitters, including acetylcholine and catecholamines.

Fig. 11. Possible natural modifications of cytosine.

As is well known, a single amino acid is coded by a sequence in the chain of three nucleotide residues—a codon. However, this coding is degenerate, since most amino acid residues are specified by more than one codon. The transmission of this information to effector ribosomal structures and its Translation into the form of an Amino Acid Sequence are carried out in stages. Through transcription, the nucleotide sequence from the non-coding DNA strand is copied onto mRNA, which, in accordance with base complementarity, becomes a copy of the sense sequence of the coding DNA strand.

The translation of this information (The conversion of the nucleotide sequence from mRNA into The amino acid residue sequence of a peptide chain) occurs on Ribosomes during Peptide Synthesis. Thus, all polypeptides synthesized within the cell contain, in a processed form, the genetic information accumulated and preserved by previous generations of organisms. This information serves as a program that determines the Properties and functions of a given organism, including its self-regulation mechanisms.

Two basic conformational states of DNA can be distinguished even under optical Microscopy: ordered Chromosomes and a dispersed chromatin network. The chromosomal conformation and packaging of DNA arise during Cell Division and ensure DNA replication. The dispersed chromatin state is characteristic of interphase in a differentiated cell, during which the Repair of Damaged DNA regions and the transcription of genetic information take place.

At present, the structure of DNA, The Genetic Code, and The Mechanism of ribosomal peptide synthesis have been studied in detail. It is only worth further emphasizing The Role of interchain and intermolecular nucleic acid complementarity, which ensures the accurate transmission of molecular information and is of fundamental importance for the reproduction of living systems.

Let us examine the chemical features of DNA Structure that provide the range of its intermolecular interactions with low-molecular-weight metabolites. The DNA macromolecule is a strongly and unevenly hydrated polyelectrolyte. The amino groups of nucleic bases are good proton acceptors and acquire a positive charge upon forming a Hydrogen bond in an acidic medium. Phosphate hydroxyl groups have a $ ext{pK}_ ext{a}$ below 2.0 and are always negatively charged under physiological conditions. Nucleic acid Hydration plays an important role in the conformational Organization of DNA (A, B, and C Conformations) and in the solvent structure near the macromolecule's surface, especially around its major groove. In accordance with its ampholytic nature, DNA interacts with electrolyte ions, such that increasing the Ionic strength of the solution alters both the molecular volume and degree of hydration of DNA, as well as the coiling (degree of twisting) of its strands. Local interaction of DNA with polyvalent or complexing metals is of great regulatory importance. Alkaline earth and transition metals interact with the keto groups of pyrimidine bases, platinum complexes are capable of forming intramolecular cross-links with local disruption of the double-helical DNA structure, and calcium and magnesium interact with phosphate hydroxyl groups. This entire diversity of interactions forms The basis of several dynamic levels of Structural organization of DNA in chromatin. The complexation of DNA with platinum compounds underlies the cytostatic and antitumor activity of Pt(II)-based drugs (Bloomfield, 1997).

For the normal functioning of chromatin, a portion of the DNA phosphate groups must always be bound to calcium and magnesium ions. It has been found that these ions mediate the interaction of DNA with other classes of biologically active regulators—Phospholipids and acidic Peptides. They neutralize the mutual repulsion between the negatively charged groups of these components and the phosphate groups of DNA, acting as bridges for their intermolecular binding. In particular, in the presence of calcium, DNA forms complexes with phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin (Khusainova et al., 1999). On the one hand, DNA in a complex with phospholipids is partially unwound and becomes more accessible to endonuclease action. On the other hand, these DNA complexes are rod-shaped and exhibit pronounced lipophilicity. Thus, they induce liposome fusion, i.e., they play the role of a "fusogen" upon interacting with The cell membrane and can transport phospholipids and acidic peptides across The Lipid Bilayer (Kuvichkin, 2000). Not only Lipids but also their complexes with proteins have been detected in chromatin. Immunochemical analysis has revealed apolipoproteins containing proteins with molecular weights of 28 and 14 kDa in the active chromatin of hepatocytes (Panin et al., 1992).

Complexation of DNA via an intercalation mechanism—in which flat aromatic and polycyclic molecules insert into The Double Helix between adjacent base pairs, leading to the blocking of transcription—has a definite regulatory significance. Such a mechanism underlies the binding of DNA to proflavin, acridine, ethidium bromide, and certain other Antitumor Antibiotics. However, another blocking pathway is also possible: the pronounced acidic properties of DNA provide it with strong intermolecular interactions with Polyamines and basic peptides. For instance, the oligopeptide antibiotic netropsin, which contains reactive amino groups and possesses antiviral and antitumor activity, selectively binds to A—T base pairs, residing in the minor groove of the B-conformation DNA double helix. X-Ray Diffraction Analysis has revealed a high degree of electrostatic complementarity between netropsin and the phosphate groups of helical DNA (Wainer et al., 1982).