Nucleic acid-based molecules

Both approaches are simple and allow efficient encapsulation of nucleic acid-based molecules such as oligonucleotides (9,10) and pDNA (8,10,12) in liposomes that are small in size (about lOOnm diameter) and stable in circulation, protecting the cargo from degradation. In the sections to follow, we will provide a brief overview of these methods. 

When we became seriously concerned about this problem (about 1985 ), it could not be convincingly decided which of these basic alternatives was correct (Hartree-Fock or X-ray), and it was not possible to proceed further. Subseqently, however, computers developed to the point where it became possible to carry out what are now considered modest quantum mechanical calculations directly on the nucleic acid base molecules. When this was done, it was found that the main problem did not lie in the molecular mechanics approximations themselves, nor did it lie in the experimental comparison of a crystal stracture with a gas-phase structure. Rather, the major problem... 

Even if It could be shown that RNA preceded both DNA and proteins in the march toward living things that doesn t automatically make RNA the first self replicating molecule Another possibility is that a self replicating polynucleotide based on some carbo hydrate other than o ribose was a precursor to RNA Over many generations natural selection could have led to the replacement of the other carbohydrate by D ribose giving RNA Recent research on unnatural polynucleotides by Professor Albert Eschenmoser of the Swiss Federal Institute of Technology (Zurich) has shown for example that nucleic acids based on L threose possess many of the properties of RNA and DNA... 

Significant progress in the optimization of VDW parameters was associated with the development of the OPLS force field [53]. In those efforts the approach of using Monte Carlo calculations on pure solvents to compute heats of vaporization and molecular volumes and then using that information to refine the VDW parameters was first developed and applied. Subsequently, developers of other force fields have used this same approach for optimization of biomolecular force fields [20,21]. Van der Waals parameters may also be optimized based on calculated heats of sublimation of crystals [68], as has been done for the optimization of some of the VDW parameters in the nucleic acid bases [18]. Alternative approaches to optimizing VDW parameters have been based primarily on the use of QM data. Quantum mechanical data contains detailed information on the electron distribution around a molecule, which, in principle, should be useful for the optimization of VDW... 

One of the lines of approach of such an investigation is the study of analogs of nucleic acid bases. The objective here is to prepare such analogs as would be incorporated into the nucleic acid molecules on the basis of their similarity to the natural species or as could interfere at some of the steps of nucleic acid biosynthesis. 

The components of nucleic acids have been the subject of continuous DFT stud-ies61 S5,67 69. Jasien and Fitzgerald calculated dipole moments and polarizabilities for a series of molecules of biological interest including nucleic acid bases (adenine, thymine, cytosine, and guanine) and their pairs (adenine-thymine and cytosine-guanine)61. A good correlation between DFT(HL), experimental, and MP2 results was obtained for dipole moments and polarizabilities. More detailed analyses of DFT(SVWN) and DFT(B88/P86) results, which included vibrational frequencies, were reported for isolated bases and their... 

The investigations directed at the synthesis of thymine-substituted polymers demonstrate that the type of functional groups displayed by nucleic acid bases are compatible with ROMP. Moreover, the application of MALDI-TOF mass spectrometry to the analysis of these polymers adds to the battery of tools available for the characterization of ROMP and its products. The utility of this approach for the creation of molecules with the desired biological properties, however, is still undetermined. It is unknown whether these thymine-substituted polymers can hybridize with nucleic acids. Moreover, ROMP does not provide a simple solution to the controlled synthesis of materials that display specific sequences composed of all five common nucleic acid bases. Nevertheless, the demonstration that metathesis reactions can be conducted with such substrates suggests that perhaps neobiopolymers that function as nucleic acid analogs can be synthesized by such processes. 

Fenske DB, Cullis PR. Entrapment of small molecules and nucleic acid-based drugs in liposomes. Methods Enzymol 2005 391 7. 

The fluorescence of 2AP is strongly quenched by nucleic acid bases [17, 18, 24-29]. Time-correlated single-photon counting studies have shown that the interactions of 2AP with different nucleic acid bases significantly decrease the 2AP fluorescence hfetime [17, 24-29]. While the fluorescence lifetime of free 2AP in aqueous solution is about 10 ns, in double-stranded DNA the 2AP hfetimes are reduced to 30-50 ps. This effect has been used extensively to study the dynamics of mismatched base pairs [19, 21, 25, 30], local changes in dynamics of DNA molecules produced by their binding to the active sites of polymerases [26, 31-33], stacking interactions at abasic... 

Of course, the simplicity of the QM/MM operator does not imply diat it has only a small effect. Large atomic partial charges placed near the QM fragment would be expected to polarize the system strongly. Table 13.2 compares the dipole moments of the standard nucleic acid bases at the AMI level evaluated in the gas phase and in a QM/MM calculation carried out modeling aqueous solvation with a periodic box of TIP31 water molecules. Eor comparison, results from the AM1-SM2 aqueous continuum solvation model are also provided. 

Previous theoretical treatments of the transition between the helicel and random forms of the desoxyribose nucleic acid (DNA) molecule are extended to Include formally the explicit consideration of the dissociation into two separate chains and the consideration of the effects of the.ends of the chains, An approximate form for the fraction of the base pairs that are bonded is obtained in terms of two parameters, a stability constant for base pairing and a constant representing the interaction of adjacent base pairs. The matrix method of statistical mechanics proves to be adaptable to this problem. Some numerical examples are worked out for very long molecules, for which case it is found that the effect of concentration is small. 

A more practical representation of the electron distribution in a molecule can be obtained from the probability density contour maps. Isodensity contours in the molecular plane and in a plane parallel to the molecular plane at an altitude of 0.8 atomic unit have been calculated230 for three nucleic acid bases (adenine, thymine, and cytosine) from non-empirical wave functions. The first type of contour gives an overall picture of cr-bonding in the molecule, and the second characterizes the 77-electron density. 

The study of the reactivity of the nucleic acid bases utilizes indices based on the knowledge of the molecular electronic structure. There are two possible approaches to the prediction of the chemical properties of a molecule, the isolated and reacting-molecule models (or static and dynamic ones, respectively). Frequently, at least in the older publications, the chemical reactivity indices for heteroaromatic compounds were calculated in the -electron approximation, but in principle there is no difficulty to define similar quantities in the all-valence or allelectron methods. The subject is a very broad one, and we shall here mention only a new approach to chemical reactivity based on non-empirical calculations, namely the so-called molecular isopotential maps. 

The study of the nucleic acid bases is interesting because they possess many possible sites of protonation or electrophilic attack. Isopotential maps have been constructed for adenine, cytosine, and thymine.244 They may be used to study theoretically the proton affinities of the different atoms in these molecules. It is well known that protonation of cytosine, its nucleotide or nucleoside, occurs at N-394,245-247 (cf. Section II) alkylation also occurs at N-3.103-248-249 Nevertheless protonation of the oxygen of cytosine in DNA has been reported.250 The basic pA of cytosine is higher than that of adenine. The isopotential map in the molecular plane of cytosine (Tig. 8) shows that the potential well is deeper for N-3 than for 0 and the minimum for N-3 in cytosine is deeper than for any nitrogen in adenine. These maps, and their confrontation with the experimental facts have been discussed228-244... 

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