Why are nucleic acids negatively charged at physiological pH?

Why are nucleic acids negatively charged at physiological pH?

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Why do nucleic acids and mononucleotides have a negative charge physiological ph?

The phosphate group/s present in the mononucleotide or nucleic acid result in the structure having an overall slightly negative charge.

Positively charged proteins that are also present in the cell such as histones help to keep the negatively charged nucleic acid stable 'in vivo'.

Nucleic Acids

There are two types of nucleic acid, ribonucleic acid (RNA) and deoxyribonucleic (DNA) acid. RNA has a ribose and DNA is a 2'-deoxyribose.

A and B forms are right handed helices, but the Z form is left handed. The A helix bases lie farther to the outside of the helix axis and tilted, also the grooves are more nearly equal in width.

The A form has a tilt in the base pairs of about 20 degrees. The itch of the helix is reduced to 2.8 nm with 11 base pairs per turn.

We find that the Watson and Crick model is at best an approximation, as the fiber patterns of DNA have shown local variations in the angle of rotation between base pairs, the sugar conformation, the tilt of the bases, and the rise between base pairs.

The secondary structure is not homogeneous, and varies in response to the local sequence and can be changed by interaction with other molecules. Often we are given the average values. Many DNA molecules are slightly bent, as the helix axis does not follow a straight line.

The B form is suggested to be advantageous of the A form as it can accommodate a spine of water molecules lying in the minor groove conferring possibly stability.

The linkage number is the algebraic sum of the twists and writhes

The only way the linkage number of a circular molecule can be changed is by means of a topoisomerase cutting open the molecule twisting the molecule, and then sealing them back together.

All these terms have a directionality and hence can be a positive or negative number. Positive terms mean a direction to the right and negative terms mean turns to the left.

The superhelicity of DNA is expressed in terms of the super helix density.

Two major factors favors dissociation of double helices into randomly coiled single chains.
1) Electrostatic repultion between the chains. Each residue carries a negative charge that is slightly subdued by the counterions present in the medium. High ionic strength tends to stabilize the double matrix.
2) Entropy favors random coil structure with its many more random forms.

Thus the two factors can be related to the Gibbs free energy equation and written

ΔG = ΔH - TΔS (helix ⇌ random coil)

ΔH = is the electrostatic repulsion, hydrogen bonds, and wan der Waals interactions

TΔS = the possible configurations and temperature

So we see here that under normal physiological conditions that the enthalpy term in fact out weighs the entropy term.

It is possible to observe the denaturation process under UV at a λ = 260 nm for a DNA solution with changing temperature. What is observed is an increase of absorption of light as denaturation occurs. In the helical structure where the bases are packed the absorption is weaker then when denatured, known as hypochromism.

The denaturation of DNA by temperature is a very small range, known as the melting temperature, though not an apt description. DNA denaturation is a cooperative transition meaning hat the double helix does not melt bit by bit. The whole structure holds together until it is at the verge of instability and then denatures over a very narrow temperature range.

The melting temperature (Tm). depends on its (G+C)/(A+T) ratio. Because the G-C pairing forms three hydrogen bonds and each A-T pair only two, the enthalpy is greater for the melting of GC rich polynucleotides. The greater stacking energy of G-C pairs also contributes to the difference. The value of Tm corresponds to the temperature where free energy is equal to zero

Molecular Structure of Lipid a, the Endotoxic Center of Bacterial Lipopolysaccharides1

Ulrich Zӓhringer , . Ernst Th. Rietschel , in Advances in Carbohydrate Chemistry and Biochemistry , 1994

C Conclusions

Both phosphate groups of lipid A at C-1 and C-4′ may carry (polar) substituents, although examples in which the phosphate groups are free are known. The substitution of phosphate groups is often nonstoichiometric, as exemplified with N. meningitidis lipid A ( Fig. 6 ). In this interesting example the glycosylic position [GlcN(I)] and the hydroxyl group at C-4′ [GlcN(II)] both carry Etn-PP. This substitution pattern is symmetric, and careful chemical and 31 P-n.m.r. analyses have shown (73) that, in the lipid A part of this LPS, both phosphate groups at positions 4′ and 1 are nonstoichiometrically substituted by Etn-P to a similar degree (85 vs 80%). In lipid A produced with sodium acetate buffer (0.1 m NaOAc, pH 4.5, 1 h, 100 °C) the degree of Etn-P substitution at position 4′ (73%, w/w) is slightly lower, whereas substitution at C-1 is decreased to one half (45%, w/w) compared with native LPS (80%, w/w). This indicates that the pyrophosphate group of Etn-PP at C-4′ is resistant to mild acid hydrolysis, whereas that of the α-glycosylically linked Etn-PP group at C-1 is susceptible to even mild acid hydrolysis.

The extent of phosphate substitution is influenced by, for instance, the growth conditions (122–124) . It is possible that bacteria, depending on their physiological demands, are able to add or omit ionic head-groups and thereby regulate their net surface charge (113) . It is noteworthy that most of the substituents on the phosphate, such as Etn, l -Arap4N, and GlcpN carry, at neutral pH, a positively charged amino group. Their presence in the neighborhood of phosphate residues (or of Kdo in LPS) may be considered as a regulating factor, controlling the electrostatic interaction of negatively charged residues (phosphate) with such bivalent cations as Ca 2 + or Mg 2 + of the medium. The Ca 2 + and Mg 2 + ions may neutralize intermolecularly negative charges of lipid A. These interactions, therefore, appear to be of great importance for the stability and function of the bacterial outer membrane. Moreover, it has been postulated that positively charged groups in lipid A, such as l -Arap4N, significantly contribute to the resistance of certain Gram-negative bacteria (for instance P. mirabilis) to such antibiotics as polymyxin B (125) . In accordance with this concept, P. mirabilis mutants lacking l -Arap4N are highly sensitive toward polymyxin B (126) .

Khan Academy Practice Questions

Configurations (either relative or absolute) refers to the stereochemical configuration around the chiral carbon.

Due the differences in the priority of different side chains, not all amino acids have the same "Absolute Configuration" which refers to the R/S naming convention. Some amino acids are R, some are S.

Changes in pH will not alter amino acid sequence or break peptide bonds.

Primary, secondary and tertiary structure have to do with individual polypeptides

Leucine has an aliphatic side chain (carbon-carbon straight chain)

at physiological pH, leucine exists as a zwitterion

ribosomes are either free floating in cytoplasm or bound to the RER

Proteins translated freely in the cytoplasm tend to remain within the cell as cytoplasmic proteins

Proteins translated on the RER are further modified as they enter the ER, bud from it through a vesicle, move progressively through Golgi to plasma membrane

A cofactor is a nonorganic molecule whose presence is necessary for the proper function of an enzyme.

Denaturation of an enzyme will alter the kinetics of a reaction that it catalyzes.

The kinetics of a reaction can be characterized by a rate-constant.

A substrate for an enzyme is the reactant of the reaction that the enzyme catalyzes.

An enzyme and a substrate must come into close physical proximity for binding to occur, and such proximity can introduce physical forces that alter the shape of the enzyme.

Enzymes are strings of amino acids joined by peptide bonds.

Heat disrupts non-covalent interactions between amino acids in the enzyme, resulting in the denaturation of enzyme structure.

The specificity of an enzyme for its substrate is partially governed by the shape of the enzyme active site.

An enzyme active site is stabilized by non-covalent intramolecular interactions.

Non-covalent intramolecular interactions are affected by heat and pH, amongst other things.

There is a 50/50 chance each child will be male. The probability of having 2 males is .5 * .5 = .25 = 25%.

Each male receives only 1 X-chromosome and it must come from the mother since the Y chromosome can only come from the father. Since the mother is a carrier, there is a 50/50 chance she will pass on the gene for color-blindness to each male child and a 25% chance she will pass it on to both.

The probability of having zero children with blue eyes is ¾*¾=9/16.

A conservative mutation might result in conservation of the hemoglobin protein's function, therefore this is not the correct choice.

A codon deletion could potentially result in a change in the protein, however that is not the mutation causing sickle cell disease.

NO is produced by the body, and therefore is an endogenous compound.

Ethidium bromide does not cause missense mutations.

Large-scale deletions are more likely to be fatal than small-scale deletions, since more genetic material is absent.

Such large deletions could potentially reduce, not enhance, the methylation of important oncogenes.

Recall that microRNA does bind directly to mRNA, however it does not bind to promoter regions.

miRNA has no role in RNA editing or cleavage of telomeres.

A proto-oncogene can become oncogenic by deletions in the gene, or by chromosomal rearrangements.

Any increase in protein expression can contribute to oncogenicity, and this can be caused by gene amplification.

Allolactose is not involved in the relationship of RNA polymerase and DNA.

CpG methylation diminishes the oncogenic potential of cells.

CpG island methylation does not have a role in the differentiation of cells.

Binds to an operon and transcribes RNA

Displaces a repressor protein from an operon, allowing RNA polymerase to proceed in transcription

Enhances interaction between RNA polymerase and the promoter

An activator does not interact with repressor proteins.

Nor does the activator perform the actual act of transcription.

Telomeres are the 'caps' at either end of a chromatid, which protects the DNA from deterioration. It has been theorized that telomere length is inversely correlated with the aging process (shorter telomeres = aging).

The shortening of telomeres is due to the 'end replication problem'. This problem arises from the fact that DNA polymerase synthesizes DNA only in the 5' to 3' direction. One strand (the leading strand) is read without interruption, but the lagging strand must be synthesized in a discontinuous fashion.

Okazaki fragments are pieces of newly synthesized DNA along the lagging DNA strand, separated by RNA primers.

Mitochondria are the site of cellular respiration, and are essentially 'power plants' of the cell.

Lysosomes are pretty much just cellular trash cans (and recycling centers).

The ribosome is the site of translation of mRNA into protein. However it is not a site of glycosylation.

Helicases 'unzip' DNA helices.

Polymerases synthesize nucleic acids, for example DNA polymerase catalyzes the synthesis of DNA.

At vmax, the reaction is proceeding at a rate which is equal to the physiologic rate at which the enzyme can function.

At Vmax the enzyme is fully saturated, and no more free enzyme is available to bind the substrate and catalyze the reaction.

If all of the enzyme, E, is bound and operating, it must all exist in the ES state.

Cleaving a covalent bond always requires an input of energy.

Exergonic reactions are not necessarily exothermic: entropy matters as well.

Le Châtelier's principle implies that if you remove a product from a reaction at equilibrium, more product will be produced until equilibrium is reestablished.

Raising the pH of a mixture increases the amount of proton-accepting hydroxide molecules.

The free energy of a system can never be negative. Remember, free energy (G) is not the same as free energy change (∆G).

ATP hydrolysis is always spontaneous under standard conditions. It may or may not be spontaneous under conditions that deviate from those defined as standard.

Lipoproteins are the spherical carrier molecular assemblies in which lipids are transported throughout the body. Examples include HDL, LDL, and chylomicrons.

The functional properties of lipoproteins are largely determined by which apolipoproteins they express, as apolipoproteins are important signalling molecules for receptor-mediated recognition.

Apolipoproteins are simply lipoproteins unbound to lipids. Different apolipoproteins will bind lipids in a different fashion, resulting in a difference in the ratio of lipid content to protein content.

Even though they are predominantly hydrophobic, most dietary fatty acids are too large for free diffusion across membranes, which presents a kinetic barrier to their transport. Although a high FFA concentration outside of a cell may establish a gradient such that their transport into the cell is energetically favorable, the energy required for the movement of large molecules is substantial.

Coupling the transfer of large molecules to energetically favorable reactions allows this barrier to be overcome.

Three reactions allow for FA entry into the mitochondria, in a process known as the carnitine shuttle.

First, acyl-CoA synthetase links coenzyme A with the fatty acid, made favorable by the hydrolysis of two bond in ATP (to make AMP). Second, fatty acid acyl-CoA is attached to carnitine via carnitine acyltransferase I, and the acyl-carnitine enters the outer membrane.

Start simple-- a 20 carbon FA will yield 10 molecules of acetyl-CoA (20 carbons available, two carbons per acetyl-CoA). Recall that for each acetyl-CoA, the Krebs cycle produces 10 molecules of ATP.

Remember that the process of oxidizing fatty acids to form molecules of acetyl-CoA also generates energy. Each pass of β-oxidation generates one molecule of NADH and one molecule of FADH_2

To produce 10 acetyl-CoA, this fatty acid will require 9 passes of oxidation.

2.5 ATP can be generated per NADH, and 1.5 ATP per FADH_2

2.5x9= 22.5 1.5x9= 13.5 13.5+22.5+100 = 136

There are two main pathways by which amino acids are metabolized.

The two groups are defined by the end products of the amino acids degraded.

One group is degraded to acetoacetyl-CoA and/or acetyl-CoA. The other is degraded to pyruvate, α-ketoglutarate, succinyl-CoA, fumarate and/or oxaloacetate.

Oxaloacetate (OAA) is an important intermediate in the citric acid cycle and in gluconeogenesis.

OAA is principally formed from either malate or pyruvate.

Ketogenic amino acids, as well as fatty acids, are principally metabolized to form acetyl-CoA.

Glucogenic amino acids enter the citric acid cycle at multiple points, with the common theme of ultimately producing glucose.

Many glucogenic amino acids are catabolized to pyruvate, or directly to form OAA.

What is Nucleic Acid?

Nucleic acids are macromolecules they form via the combination of thousands of nucleotides. They have C, H, N, O and P. There are two major types of nucleic acids in biological systems they are the DNA and RNA. They are the genetic material of an organism and are responsible for passing genetic characteristics from generation to generation.

Further, these compounds are important to control and maintain cellular functions. A nucleotide contains three units they are the pentose sugar molecule, nitrogenous base, and phosphate group. According to the type of pentose sugar molecule, nitrogenous base, and the number of phosphate groups, the nucleotides differ from each other. For instance, in DNA, there is a deoxyribose sugar, and in RNA, there is a ribose sugar.

Figure 02: Nucleic Acid Structure

Moreover, there are mainly two groups of nitrogenous bases they are the pyridines and pyrimidines. Cytosine, thymine, and uracil are examples for pyrimidine bases. Adenine and guanine are the two purine bases. DNA has adenine, Guanine, cytosine, and thymine bases, whereas RNA has A, G, C and uracil (instead of thymine).

In DNA and RNA, complementary bases form hydrogen bonds between them. Likewise, in those, adenine to thiamine (or uracil if it is RNA) and guanine to cytosine are complementary to each other. The phosphates groups can link with the –OH group of carbon 5 of the sugar. Nucleic acids form via combining nucleotides with phosphodiester bonds removing water molecules.

Macromolecular Architectures and Soft Nano-Objects Polylysine dendrimers

Polylysine dendrons were first developed by Denkewalter et al. 100 in the beginning of the 1980s, employing solid-phase synthesis to generate a 10th-generation polypeptide dendron. These structures were revisited by Tam et al., who reported the divergent construction of a third-generation unsymmetrical polylysine dendron, using conventional solid-phase peptide synthesis (SPPS). 101 The dendrons were accomplished using a phenylacetamidomethyl-functional PS support with a β-Ala spacer. Prior to cleavage, the dendrons were end-capped with a peptide sequence derived from the human T-cell antigen receptor. 101 Polylysine dendrons have also been achieved on PEGA 102,103 as well as Tentagel resins. 104,105 The convergent solid-phase synthesis of polylysine dendrons on silica support has been reported in order to evaluate the product as a chiral stationary phase in chromatography. 106 The results indicate higher surface coverage with increasing generation. The straightforward and easily adapted solid-phase synthesis of polylysine dendrimers makes solution-based construction unnecessary. Nonetheless, the divergent growth of fourth-generation polylysine dendron was accomplished using PEG as a hydrophilic tail, which facilitates simple purification and isolation of the product. 107 The convergent growth approach has also been employed to construct third-generation polylysine dendrons decorated with eight mannose or galactose groups and a single fluorescein isothiocyanate (FITC) dye. 108 Supramolecular structures based on polylysine dendron were first reported by Hirst et al., 109 who described a unique gelation effect based on hydrogen bonding between the carboxylic group at the focal point and diaminododecane used as a gelator. The ratio between the two components, the chirality of the dendrons, 110 and the length of the diamine spacer 111 were found to significantly influence the structure on a microscopic and macroscopic level. Supramolecular chemistry was also successfully employed to render polylysine dendrimers from dendron derivatives. The dendrimers were assembled using the covalently attached crown ether and ammonium cationic guests and disassembled using potassium cations ( Figure 22 ). 24

Figure 22 . Supramolecular chemistry of polylysine dendrimers as described by Hirst et al. 109

Basic principles of gel electrophoresis to separate nucleic acids

Gel electrophoresis is a common laboratory technique in molecular biology to identify, quantify, and purify nucleic acids. Because of its speed, simplicity, and versatility, the method is widely employed for separation and analysis of nucleic acids. Using gel electrophoresis, nucleic acids in the range of approximately 0.1–25 kbp can be separated for analysis in a matter of minutes to hours, and separated nucleic acids can be recovered from the gels with relatively high purity and efficiency [1,2].

The technique involves the application of an electrical field to mixtures of charged molecules to cause them to migrate, on the basis of size, charge, and structure, through a gel matrix. The phosphate groups of the ribose-phosphate backbones of nucleic acids are negatively charged at neutral to basic pH (Figure 1A). As such, each nucleotide carries a net negative charge, meaning the overall charge of a nucleic acid molecule is proportional to the total number of nucleotides or its mass. In other words, DNA or RNA molecules carry a constant charge-to-mass ratio. As a result, their mobility in gel electrophoresis is determined mainly on the basis of size when they have comparable structure (learn more about how nucleic acid structure impacts migration). Therefore, when subjected to an electrical field, nucleic acids migrate from the negative electrode (cathode) toward the positive electrode (anode), with shorter fragments moving more rapidly than longer ones, resulting in separation based on size (Figure 1B).

Figure 1. (A) Net negative charges carried by a nucleic acid chain. (B) Separation of nucleic acid fragments of varying lengths in gel electrophoresis.

Furthermore, the migration distances of nucleic acids in gel electrophoresis generally display a predictable correlation with their sizes, enabling calculation of the size of nucleic acids in a given sample. For linear double-stranded DNA fragments, migration distance is inversely proportional to the log of the molecular weight, within a certain range (Figure 2A) [3]. For approximate sizing, migration distances are commonly compared to samples containing molecules of known sizes (molecular weight standards, sometimes referred to as “ladders”) which are often included in the gel run. A widely accepted model of nucleic acid mobility through a gel is “biased reptation”— migration biased towards the applied electrical force and involving a snaking movement where the leading edge pulls the rest (Figure 2B) [4,5]. This model has been visualized by fluorescence microscopy [6].

Figure 2. Mobility of nucleic acids in gel electrophoresis. (A) Correlation of size and migration of linear double-stranded DNA fragments. (B) Biased reptation model.

DNA is not isolated in the body, so what keeps it stable while being charged?

The main molecules in charge of that are proteins called histones. They have alkali features and positive charge, and so, they neutralize these negative charges. On the other hand, that's not the main point of histones. Histones play a really important key role in the regulation and compaction of DNA within the nucleus of the cell, and are important targets of diverse molecules that want to alter DNA structure and function:

Lehninger 5th edition.Figure 24-26


Development of functionalised nano-tools for biomedical research and therapy is explosively progressing field and various strategies are applied for refining NPs, from both the vector and the biologically active cargo side. 1–4 Among highly promising approaches is application of CPPs 5–7 as efficient carrier vectors for the delivery of different functional nucleic acid (NA) molecules, e.g. plasmid DNA, mRNA, siRNA, miRNA, splicing correcting oligonucleotides etc. 8 Once transfected, these NAs can modulate the flow of genetic information in the cells and, consequently, alter cellular responses in target sites. 9 CPPs are able to condense NA by electrostatic complexing after simple mixing step and effectively transport compacted NA into the cells, mostly by harnessing various endocytic pathways. Delivery of NAs with CPPs in vitro results in efficient and homogeneous uptake of the complexes by cells and in a functional effect of NA, e.g. expression of exogenous gene from pDNA or silencing of targeted gene by siRNA. However, application of the same delivery system in animal models in vivo has usually yielded much lower efficiencies so far, 4,10 which is also characteristic for lipid-based 11 and other types of nanoparticles. 12,13 Still, encouragingly, several break-through studies regarding applicability of CPP-mediated transport in vivo have been published recently. 14–16

Nowadays, it is well established that various proteins rapidly coat the NPs engineered for drug delivery after the contact with biological fluids (e.g. after contact with bloodstream in case of intravenous administration). 17–19 Formation of a protein corona provides the pristine NPs with a new biomolecular interface for interaction with blood cells and lining endothelium, and for detection by specialised phagocyte cells with subsequent elimination. 20,21 The components of protein corona rather than the nanoparticle per se are typically recognized by receptors on cell surface. For example, in the case of DNA-lipid nanoparticles, vitronectin enriched on particles associates with αvβ3 integrins on cancer cells. 22 Analogously, for targeting to hepatocytes, interaction with apolipoproteins is required for some siRNA lipoplexes. 23,24 Remarkably, the liver tropism of the first siRNA drug, Onpattro, is based on the ability of lipid nanoparticle to recruit into its PC apolipoprotein E that enables specific hepatocyte targeting. 11,25,26 Recently, the preformed protein corona was harnessed to convert nanoparticles targetable to tumour cells. For that, particles were coated with tumour-specific antibodies and human serum albumin that helps to prevent phagocytosis of the particles. 27–29

On the other hand, protein corona can interfere with targeted delivery by masking the ligand on the nanoparticle surface that specifically interacts with endocytosis triggering receptors. 30,31 The composition and properties of forming protein corona highly depend on one hand on the type and properties of nanoparticles, like composition, size, charge, hydrophobicity etc., 10,32–35 and on the other, on environmental factors, like temperature, 36,37 incubation time 17,38 and, especially, on the biofluid type, 39,40,41 origin and disease 42,43 . In general, protein corona on the smaller nanoparticles is thinner and less dense than on the larger ones. 44,45 In addition, cationic nanoparticles are cleared from circulation much faster than neutral or anionic counterparts. 46 Thus, one of the potential obstacles for cellular uptake of CPP-nucleic acid nanoparticles in vivo might be their inefficient association with cells due to the formation of protein corona on the surface of particles after introduction into physiological environment. 47

Condensation of differently sized nucleic acid molecules to nanoparticles using various cell-penetrating peptides has been well documented. 48–51 Although the properties of such nanoparticles might significantly change after formation of protein corona on its surface, the composition of protein corona and its impact have not been studied so far. Only the increase of the nanoparticle’s size in the presence of serum 48,50,52–54 and the decrease in protein quantity associating with particle upon reducing CPP/nucleic acid molar ratio have been reported. 55

In this study, we characterised the composition and effect of the protein corona that formed on the surface of CPP-nucleic acid nanoparticles. Analysed particles contained plasmid DNA (pDNA) or splice-correcting oligonucleotide (SCO) that were non-covalently complexed with three CPPs: PepFect 14 (PF14), PF14 modified with a 22-carbon fatty acid tail (C22-PF14) 56 or NickFect 55 (NF55). 57 We studied the formation of protein corona on different nanoparticles in bovine serum as a representative of cell culture systems, in murine serum as a typical animal model used in the development and testing of such nanoparticles, and in human serum as a representative of the actual target for drug development (Schema 1). We observed that dissimilar protein corona forming in different sera translates to unequal uptake of studied nanoparticles by cultured cells, and varying biological response to nucleic acid cargo. Our results emphasize that, as expected, the features of protein corona on CPP-nucleic acid nanoparticles vary in different animal models and cell culturing conditions, and these might represent the underlying cause for discrepant results obtained in in vitro and in vivo systems respectively.

Condensation of nucleic acid (NA) to nanoparticles by cell-penetrating peptide (CPP), and formation of protein corona on nanoparticles in serum containing media.

Is DNA an acid because of phosphate group - (Mar/09/2010 )

why is DNA or RNA are acids for having phosphate group. Is it like negatively charged are acids?

Yes it is the same like other acids. The base is hydrophobic which dosent have any charge, the sugar is hydrophilic and it is only the phosphate groups that give it a over all a net negative charge.

If you need further calrification, please give a mail at [email protected]

Hi snemani1177, welcome to the BioForums!

As you know, DNA is composed of a double-stranded string of nucleotides (A, T, C, and G), each contributing a deoxyribose sugar, a phosphate ion, and a nitrogenous base. When assembled, the exposed face of a DNA molecule is composed of alternating phosphates, which are proton donors at neutral pH (thus, at neutral pH, they're negatively charged, or acidic). The basic portion of each nucleotide is tied up inside the helix, and thus does not react with the environment, thus the overall charge of the molecule is negative, or acidic.

Watch the video: What is DNA and How Does it Work? - Basics of DNA (May 2022).