A theoretical study of the interaction of guanine and cytosine with specific amino acid side chains.

Quantum-mechanical computations are performed on the in vacuo and in water interactions between the purine bases guanine and cytosine and the side chains of the amino acids arginine, lysine, glutamic acid and glutamine. The results predict that while guanine should be the more strongly interacting base both in vacuo and in water, lysine should be the most strongly interacting amino acid in vacuo and arginine the most strongly interacting amino acid in water solvent. The theoretical results on the interactions in water agree satisfactorily with experimentation.

A theoretical study on the specificity of tetramethylammonium versus monomethylammonium binding to the active site of a phosphorylcholine antibody.

In order to account for the specificity of binding of tetramethylammonium (TMA) versus monomethylammonium (MMA) to the combining site of phosphorylcholine specific immunoglobulin IgA H-8, theoretical computations are performed on the interaction energies of these cations with varying combinations of amino acid side chains, present or suspected to be present at that site. The dehydration of the cations, which represents a prerequisite for their binding is about 20 kcal/mol more difficult for MMA than for TMA. The interaction energies with the binding site are somewhat higher for MMA than for TMA. For some combinations of the amino acid side chains, their difference is smaller than the difference in the dehydration energy. Such combinations ensure preferential binding of TMA.

Molecular orbital calculations on the conformation of phosphodiesters. An extended correlation between the geometry and the conformation of the phosphate group.

An extension of our previous correlation (C.R. Acad. Sci. Paris, Ser. D (1973) 277, 2257; Biochim. Biophys. Acta (1974) 340, 299) between the geometry of the phosphate group and the conformation of phosphodiesters established by PCILO computations, shows that the probability of gauche-trans or trans-gauche conformations should become appreciable for low values (100-101) of the 33'-P-O5', angle and may even become predominant when the C-O-P angles have also a low value (congruent to 117 degrees). The results agree satisfactorily with available X-ray crystallographic data.

Molecular orbital studies on the conformations of 8-amino- and 8-dimethylaminoadenosine 5'-monophosphate.

The quantum mechanical PCILO method has been applied for the determination of conformational properties of 8-amino- and 8-dimethylaminoadenosine 5'-monophosphate. Contrary to other 8-substituted nucleotides the amino derivative shows a preference for an anti arrangement about the glycosidic bond. This conformation is stabilized by an intramolecular hydrogen bond between the purine and the exocyclic group. 8-dimethylamino-adenosine-5'-monophosphate adopts the syn conformation with slightly rotated dimethylamino group. There is, however, a local minimum for the anti form associated with the unusual value of chiCN = 300 degrees. This minimum is probably populated when the nucleotide is bound to lactate dehydrogenase apoenzyme. No particularly strong interactions are necessary for the stabilization of the anti form. The computations account satisfactorily for the available experimental data.

Molecular orbital studies on the structure of nucleoside analogs. I. Conformation of 8-azapurine nucleosides.

PCILO (perturbative configuration interaction using localized orbitals) computations have been carried out for the conformational properties of 8-azapurine nucleosides. The results indicate an anti conformation for Xcn and a gg conformation for phiC(4')-C(5') for C(2')-endo 8-aza analogs compared to the syn and gg conformation for the corresponding purine nucleosides. For C(3')-endo sugar puckering, both molecules prefer the syn conformation due to intramolecular hydrogen bonding between O(5')-H of the sugar and N(3) of the base, the preference being more profound in 8-aza analogs. The crystallographic conformation 8-azaadenosine has been attributed to crystal forces. The available NMR data on 8-azapurine nucleosides are in agreement with the PCILO predictions.

Theoretical study of the hydration of B-DNA.

A theoretical study of the hydration of the B-form of DNA has been carried out using empirical potential energy functions. In the first stage the hydration scheme of a model compound representing the B-DNA has been determined and the results have been shown to agree to a large extent with those of refined ab initio SCF computations. In the second stage, the stabilization energy due to the presence of water in the first hydration shell was computed by considering the hydrated helix as a supermolecule. The computations indicate appreciable stabilization. The different components contributing to the overall stabilization are determined and analysed.

A molecular orbital investigation of the conformation of transfer RNA.

The PCILO method has been used for a theoretical exploration of the conformational properties of tRNAPhe with respect to the phosphodiester torsion angles. The computations were based on the utilisation of the dinucleoside triphosphate model and took into account the different combinations of sugar puckers and different conformations about the C4'-C5' bond. The dependence of the (omega'-omega) conformational energy maps upon these factors was specified. A detailed comparison is carried out between the theoretical results and experimental data on the crystal structure of tRNAPhe produced by four different groups of investigators.

Theoretical NMR study of the pre-melting transition in the d-(CGCGAATTCGCG) and d-(CGCGTATACGCG) self-complementary duplexes.

The difference between their shielding in a B-DNA duplex and in the single strand having the same conformation has been calculated for all base protons of the dodecamers d-(CGCGAATTCGCG) and d-(CGCGTATACGCG). The calculated chemical shift variations reproduce the qualitative features of the shifts which occur during the pre-melting of the helices. This agreement shows that the pre-melting mechanism consists mainly of a lengthening of the hydrogen bonds between the two strands (in line opening) and that the conformation of the ribophosphate backbone and the orientation of the bases do not undergo major modifications during the first step of the melting.

Groove selectivity in the interaction of 9-aminoacridine-4-carboxamide antitumor agents with DNA.

Theoretical quantitative evaluation of the intercalative binding to DNA of the new antitumor drug 9-aminoacridine-4-carboxamide indicates that, in contradiction with a recently proposed model, the compound should show specificity for interaction with the major (and not minor) groove of GC sequences.

Modelling basic features of specificity in DNA-aureolic acid-derived antibiotic interactions.

The nonintercalative groove binding of a simplified model of olivomycin, to sequences d(CGCGCGC)2, d(TATATAT)2, and d(CICICIC)2 is investigated. A significant preference is displayed for the minor groove of the d(CG) sequence. This is due predominantly to the formation of H-bonds between the hydroxyl groups on the aglycone of the drug and the 2-amino group of the central guanine of the oligonucleotide.

Theoretical studies on the interaction of proteins and nucleic acids. I. The binding of beta-pleated sheets to A- and B-DNA.

A theoretical investigation of the interaction between a beta-ribbon consisting of two glycine hexapeptides and DNA in its A and B conformations is presented. A refined semi-empirical energy formula and a sophisticated energy minimization technique are used to optimize the complex, taking into account the DNA-beta-ribbon interaction, the full flexibility of the oligopeptide chains and of the positions of the DNA screening counterions. A considerable flexibility of the beta-ribbon is demonstrated, which allows the polypeptide fragment to interact comfortably with both forms of DNA considered and with different base-pair sequences. The results are discussed in connection with the general problem of DNA-protein recognition.

Theoretical studies on the interaction of proteins and nucleic acid. II. The binding of alpha-helix to B-DNA.

Interactions between B-DNA and homopolymeric alpha-helices of glycine, alanine, serine, asparagine and aspartic acid have been studied theoretically. The complexation energy has been minimised taking into account the interactions between DNA and the polypeptides as well as the internal energy of the alpha-helix and the interaction energy of counterions with the complex. The results obtained indicate the important role of strong hydrogen bonds between the peptide side chains and nucleic acid phosphate groups, these bonds being much stronger than specific interactions with the base-pairs. The formation of these structural bonds depends on the size of the alpha-helix, which in turn determines whether bridging across the major groove is possible. The steric role of the methyl group of thymine in orienting the peptide helix and the role of DNA screening cations in complex stabilization are also significant.

The electrostatic field of the component units of DNA and its relationship to hydration.

The electrostatic fields of the subunits of DNA are presented and compared with the corresponding electrostatic potentials. Differences are observed between these two properties, due to their different dependence on distance, which are of considerable interest since, whereas the potential may be used in studying the reactivity of molecules towards charged species, the field can be a similar guide to attack by neutral, dipolar molecules such as water. It is demonstrated, for the example of the purine and pyrimidine bases, that the field may indeed be used to detect preferential hydration sites.

Intrinsic electrostatic properties and base sequence effects in the structure of oligonucleotides.

Molecular electrostatic potentials and steric accessibilities are calculated for Dickerson's dodecanucleotide CGCGAATTCGCG and compared with those for the 'inverted' sequence TATAGGCCTATA. The results are used to distinguish between properties due to base sequence (the location of the deepest potential minimum in the minor groove of A-T sequences and in the major groove of G-C sequences) and those due to the finite length of the oligonucleotide (location of the deepest potential in the central part of the oligonucleotide).

Electrostatics of Polymorphic DNA.

The molecular electrostatic potential (MEP) and the molecular electrostatic field (MEF) are associated with significantly different patterns of distribution in the nucleic acids and their constituents. In particular, a) while the values of the minimal potentials at the reactive sites of the bases or at the phosphates increase manyfold when going from the subunits to the double helix, the values of the field undergo only very small changes under the same circumstances and b) while the deepest potentials are located in the grooves of the double helix, the greatest fields are concentrated on the phosphates of the backbone. They are also influenced differently by such environmental factors as counterion screening: while the absolute values of the potentials are profoundly reduced, the fields are increased with respect to those of the unscreened acids. MEP and MEF also govern the electrostatics of interaction of DNA with different types of species. The MEP being of particular significance in this respect for interaction with cations and the MEF for the association with neutral dipolar molecules. A number of examples are given to illustrate the significance of this situation for different conformers of DNA.

Theoretical study of the sequence selectivity of isolexins, isohelical DNA groove binding ligands. Proposal for the GC minor groove specific compounds.

A theoretical study is presented of complex formation between DNA fragments of different base sequences and isolexins, "isohelical base reading polymers", formed of heteroaromatic pentagonal rings joined by appropriate linkers. Extensive computations are performed for the isolexin composed of the furan-pyrrole-furan sequence. They involve charged ligands with propioamidinium groups at both ends as well as neutral molecules with terminal methyl, carbonyl and amino groups. Two different groups (C = O and NH) are used as linkers between the base reading moieties. The role of these elements on the binding preference of the ligands has been examined. The results show that the mere possibility of formation of hydrogen bonds between a ligand and the nucleic acid bases is not sufficient to ensure its binding specificity which is determined largely by the interplay of electrostatic factors. Thus the dicationic isolexins uniformly prefer AT sequences. For the neutral isolexins the nature of the groups forming the linkers is a major factor in defining the specificity, although these groups do not participate directly in the interaction with DNA. The C = O linkers favour binding to AT sequence while the N-H linkers permit preferential binding to the GAG sequence. Finally, for the first time in theoretical computations, a ligand is proposed which should bind preferentially to the minor groove of GC sequences: this ligand is a neutral isolexin composed of three furan rings linked by two N-H groups. This ligand is considered as an improvable prototype. Altogether the results presented open the path for the designing of minor groove ligands specific for any desirable DNA base sequence.

Sequence selectivity, a test of the nature of the covalent adduct formed between benzo[a]pyrene and DNA.

A theoretical study is presented of the energetic and structural properties of covalent adducts of benzo[a]pyrene and a DNA fragment. Energy optimisation is performed with the use of minimiser with constraints and an advanced semiempirical energy formula. Three types of adducts are studied: an external complex with the benzopyrene located in the DNA minor groove and two types of intercalative complexes with the carcinogen situated on the 3' side and 5' side of the covalently bound guanine. For each of the adducts the effects of DNA base sequence are examined. It is shown that the results for the intercalative complex with the carcinogen situated on the 5' side of the modified guanine correlate with the experimentally determined sequence preference.

The dependence of the surface electrostatic potential of B-DNA on environmental factors.

The electrostatic potential of B-DNA is calculated on its surface envelope for two homopolymeric base pair sequences using models representing the effects of both counterion binding and of aqueous solution. The influence of these two factors on the resulting potentials is established and the significance of calculations which omit such effects is discussed.