Anil Saran

Quantum-Mechanical Studies on the Conformation of Nucleic Acids and Their Constituents

Publisher Summary This chapter discusses the results of the quantum-mechanical computations of the conformational properties of nucleic acids and their constituents, comparing the results obtained by different methods among themselves with the results of the empirical computations, and with the available experimental data as obtained by different techniques, both in the solid state and in solution. It reviews that “empirical” procedures consist of partitioning the potential energy of the system into several discrete contributions such as nonbonded interactions, electrostatic interactions; barriers to internal rotations, hydrogen-bonding, which are then evaluated with the help of empirical formulas deduced from studies on model compounds of small molecular weight. In the simplest approximation of these procedures, the problem is limited to the evaluation of allowed or forbidden contacts, with the help of van der Wads radii. The quantum-mechanical methods also aim at a direct evaluation of the total molecular energy, associated with the different atomic configurations of the system, and thus at a direct prediction of the preferred molecular conformations. The practical realization of this scheme became possible only recently, owing to the development of the all-valence-electrons and all-electron-molecular-orbital methods. The chapter reviews that quantum mechanics have been extensively used in the field of the conformational properties of the nucleic acid and their constituents, and that yielded the most complete and the most satisfactory description of the subject.

Molecular orbital calculations on the conformation of nucleic acids and their constituents: III. Backbone structure of di- and polynucleotides

Abstract Molecular orbital calculations, using the all-valence electrons method PCILO (Perturbative Configuration Interaction using Localized Orbitals), carried out previously for the glycosyl torsion angle χ cn have now been extended to the principal torsion angles of the backbone structure of polynucleotides, Ψ, Ф, ω, ω′ and Ф′ (in the notations of Sundaralingam). Conformational energy maps have been constructed for the four combinations of two consecutive angles: (ω′-ω), (Ф′-ω′), (ω-Ф) and (Ф-Ψ) with appropriate values adopted for the torsion of the angles not involved in the particular map under construction. The results of the PCILO computations are compared with data available from X-ray crystallography of related compounds and with similar calculations carried out by the empirical methods and by a simple quantum mechanical procedure (Extended Huckel Theory).

Molecular orbital calculations on the conformation of nucleic acids and their constituents. IV. Conformations about the exocyclic C(4′)-C(5′) bond

Abstract Quantum-mechanical computations carried out by the PCILO (perturbative configuration interaction using localized orbitals) method predict that the gg conformation of the exocyclic C(4′)-C(5′) bond should be the most stable one in purine and pyrimidine nucleosides and nucleotides, irrespective of the puckering of the sugar, at least as long as these puckerings belong to the most frequent C(3′)-endo, C(2′)-endo and C(3′)-exo categories. This prediction is in agreement with recent results of NMR studies in solution and with a large body of X-ray crystallographic results, to the extent that the cases in which the compounds exist in the crystal in the gt or tg forms may reasonably be attributed to the effect of environmental forces. The results also provide evidence for a number of fine details of the situation. A particularly significant result concerns the demonstration of an analogy between the behavior of the C(3′)-endo pyrimidine nucleosides and C(2′)-endo purine nucleosides on the one hand (strong preference for the gg conformers in both types) and between the C(2′)-endo pyrimidine nucleosides and C(3′)-endo purine nucleosides on the other (weak preference for the gg conformers in both types). The precision of the PCILO results is much greater than that of empirical or EHT (Extended Huckel theory) computations.

Molecular orbital calculations on the conformation of nucleic acids and their constituents: IX. The geometry of the phosphate group: Key to the conformation of polynucleotides?

Abstract The PCILO (ω′—ω) conformational energy maps of dimethyl phosphate constructed with different geometries of the phosphate group corresponding to the known crystal structures of U 3′ p 5′ A and A 2′ p 5′ U show that the global minimum of each map corresponds to the observed crystallographic conformation of the dinucleoside monophosphate having the same phosphate geometry. This result indicates that the conformational preferences of these relatively large molecules are determined essentially by the geometrical properties of the phosphate group. In particular it is shown in this study that the right-handed helical conformation of the dinucleoside monophosphates is favoured when the O 5′ PO(I) and O 3′ PO(II) valence angles have values greater than their symmetrical value (i.e. the value in the corresponding symmetrical dimethylphosphate) and that the left-handed helical conformation is favoured when these same valence angles have values smaller than their symmetrical value. A further confirmation of this rule is accomplished by analysing the phosphate group geometry in the crystal structures of diethyl phosphates. Such an analysis shows that the agreement between the observed conformations and those predicted by the rule is excellent. Ab initio calculations performed on a few selected geometries of dimethyl phosphate confirm the PCILO results. They also demonstrate that the conformation of the methyl groups has an influence on the overall stability.

Quantum chemical studies on the conformational structure of nucleic acids III. Calculation of backbone structure by extended Hückel theory

Abstract Extended Huckel theory has been used to calculate the torsional angles (φ′, ω′, ω, φ, ψ) for the sugar phosphate bonds which lead to stable conformations. The predicted conformations are in good agreement with the experimental observations on nucleosides, nucleotides and polynucleotides. It appears that in a double helical structure, the nonbonded and “stacking” interactions provide the stability to the conformational structure of each strand and these strands are then struck together by hydrogen bonds. The unwinding of the double helix, most likely, occurs through internal rotations about O3′-P and/or P-O5′ bonds.

Quantum chemical studies on the conformational structure of nucleic acids I. Extended Hückel calculations on d-ribose phosphate☆

Abstract The extended Mickel theory has been used to predict the stable conformations of d -ribose phosphate. The results have been compared with those obtained from “contact criterion” and from classical potential functions.

Molecular orbital calculations on the conformation of nucleic acids and their constituents XI. The backbone structure of (3′–5′) and (2′–5′)-linked diribose monophosphates with different sugar puckers

Abstract The PCILO (ω′-ω) conformational energy calculations on (3′-5′) and (2′-5′)-linked diribose and (3′-5′)-linked dideoxyribose monophosphates with different sugar puckers and different geometries of the phosphate group corresponding to the known crystal structures of U3′p5′A and A2′p5′ U show that the disugar backbone provides stable arrangements in the right and left-handed folded conformations. The occurence of these folded conformations depends to a large extent on the geometry used for the phosphate group and generally the following rule remains valid: the right-handed folded conformation is favored when the O5′PO(I) and O3′PO(II) valence angles are greater than their symmetrical value while the left-handed folded conformation is favored when these valence angles are smaller than their symmetrical value. In a few cases associated with specific combinations of the linkage and the sugar puckers the preferred folded conformations are changed. As far as the effect of linkage is concerned, the greatest probability of occurence of the right-handed folded conformation is found generally for (3′-5′)-linked dimers and the greatest probability of occurence of the left-handed folded conformation for (3′-5′)-linked deoxyribose and (2′-5′)-linked ribose dimers.

Quantum chemical studies on the conformational structure of nucleic acids. II. EHT and CNDO calculations on the puckering of D-ribose.

Abstract The extended Huckel theory (EHT) and complete neglect of differential overlap (CNDO) methods have been used to calculate the minimum energy conformations of the sugar rings in d -ribose. A C3′-endo structure with a small puckering of C2′ atom on the opposite side is predicted to be the most stable structure. Most of the experimental data lie in the theoretically predicted regions of high stability. The conformational structure of the chain depends, to a certain extent, on the conformations of the sugar ring.

Exploring the binding of HIV-1 integrase inhibitors by comparative residue interaction analysis (CoRIA).

Since the recognition of HIV-1 integrase as a novel and rational target for HIV therapeutics, remarkable progress has been made in the development of integrase inhibitors. Computational techniques have played a critical role in accelerating research in this area. However, most previous computational studies were based solely on ligand information. In the present work, we describe the application of one of our recently developed receptor-based 3D-quantitative structure activity relationships (QSAR) methods, i.e. comparative residue interaction analysis (CoRIA), in exploring the events involved in ligand-integrase binding. In this methodology, the non-bonded interaction energies (van der Waals and Coulombic) of the inhibitors with individual active site residues of the integrase enzyme are calculated and, along with other thermodynamic descriptors, are correlated with biological activity using chemometric methods. Different combinations of descriptors were used to develop three types of QSAR models, all of which were found to be statistically significant by internal and external validation. This is the first report of such a dedicated receptor-based 3D-QSAR approach being applied to comprehend the integrase–inhibitor recognition process. In addition, the study was performed on 13-different series of inhibitors, thereby exploring the most structurally diverse data set ever used in understanding the inhibition of HIV-1 integrase. The major advantage of this technique is that it can quantitatively extract crucial residues and identify the nature of interactions between the ligand and receptor that modulate activity. The models suggest that Asp64, Thr66, Val77, Asp116, Glu152 and Lys159 are the key residues influencing the binding of ligands with the integrase enzyme, and the majority of these results are in line with earlier studies. The approach facilitates easy lead-to-hit conversion and design of novel inhibitors by optimisation of the interaction of ligands with these specific residues of the integrase enzyme.

Conformational structure of glycerol trivalerate and its relation to phospholipids: Studies by NMR and potential energy calculations

Abstract The structure of a model lipid (glycerol trivalerate, GTV) has been investigated by 1H and 13C NMR, and energy calculations based on classical potential functions (CPF). The structure of glycerol-ester pivot in GTV is characterized by a dynamic equilibrium between two dominant conformations. One of the two conformations (SA) is similar to the reported crystal structure of triglycerides β-triaurin and β-tricaprin and has the following conformational angles: θ 1 = 52°, θ 3 = 46°, α 1 = 208°, β 1 = 156° and γ 1 = 186° . The other conformer (SB) is similar to the reported crystal structure of β and γ chains in 1,2- dilauroyl -D,L- phosphatidylethanolamine and has the conformational angles: θ 1 = 287°, θ 3 = 155°, α 1 = 195°, β 1 = 85° and γ 1 = 194° . The ester groups acquire a rigid planar conformation ( α 2 , β 2 , γ 2 = 180° ), while the potential energy curves for rotation around the chemical bonds OCOCCC( α 3 , β 3 and γ 3 ) indicate a high degree of flexibility. The hydrocarbon chains show a distribution of the gauche and trans conformations around CCCC bonds with a preference for the trans arrangement by almost 0.8 kcal/mol. The conformational picture of the hydrocarbon chains and glycerol moiety in GTV is very similar to that in phospholipids. These results indicate caution in using the reported crystal structure of 1,2- dilauroyl -D,L- phosphatidylethanolamine as the only model for the organization of lipid molecules in biological membranes.