Biologically important conformational features of DNA as interpreted by quantum mechanics and molecular mechanics computations of its simple fragments.

Deciphering the mechanism of functioning of DNA as the carrier of genetic information requires identifying inherent factors determining its structure and function. Following this path, our previous DFT studies attributed the origin of unique conformational characteristics of right-handed Watson-Crick duplexes (WCDs) to the conformational profile of deoxydinucleoside monophosphates (dDMPs) serving as the minimal repeating units of DNA strand. According to those findings, the directionality of the sugar-phosphate chain and the characteristic ranges of dihedral angles of energy minima combined with the geometric differences between purines and pyrimidines determine the dependence on base sequence of the three-dimensional (3D) structure of WCDs. This work extends our computational study to complementary deoxydinucleotide-monophosphates (cdDMPs) of non-standard conformation, including those of Z-family, Hoogsteen duplexes, parallel-stranded structures, and duplexes with mispaired bases. For most of these systems, except Z-conformation, computations closely reproduce experimental data within the tolerance of characteristic limits of dihedral parameters for each conformation family. Computation of cdDMPs with Z-conformation reveals that their experimental structures do not correspond to the internal energy minimum. This finding establishes the leading role of external factors in formation of the Z-conformation. Energy minima of cdDMPs of non-Watson-Crick duplexes demonstrate different sequence-dependence features than those known for WCDs. The obtained results provide evidence that the biologically important regularities of 3D structure distinguish WCDs from duplexes having non-Watson-Crick nucleotide pairing.

[Analysis of Conformational Features of Watson-Crick Duplex Fragments by Molecular Mechanics and Quantum Mechanics Methods].

It is generally accepted that the important characteristic features of the Watson-Crick duplex originate from the molecular structure of its subunits. However, it still remains to elucidate what properties of each subunit are responsible for the significant characteristic features of the DNA structure. The computations of desoxydinucleoside monophosphates complexes with Na-ions using density functional theory revealed a pivotal role of DNA conformational properties of single-chain minimal fragments in the development of unique features of the Watson-Crick duplex. We found that directionality of the sugar-phosphate backbone and the preferable ranges of its torsion angles, combined with the difference between purines and pyrimidines. in ring bases, define the dependence of three-dimensional structure of the Watson-Crick duplex on nucleotide base sequence. In this work, we extended these density functional theory computations to the minimal' fragments of DNA duplex, complementary desoxydinucleoside monophosphates complexes with Na-ions. Using several computational methods and various functionals, we performed a search for energy minima of BI-conformation for complementary desoxydinucleoside monophosphates complexes with different nucleoside sequences. Two sequences are optimized using ab initio method at the MP2/6-31++G** level of theory. The analysis of torsion angles, sugar ring puckering and mutual base positions of optimized structures demonstrates that the conformational characteristic features of complementary desoxydinucleoside monophosphates complexes with Na-ions remain within BI ranges and become closer to the corresponding characteristic features of the Watson-Crick duplex crystals. Qualitatively, the main characteristic features of each studied complementary desoxydinucleoside monophosphates complex remain invariant when different computational methods are used, although the quantitative values of some conformational parameters could vary lying within the limits typical for the corresponding family. We observe that popular functionals in density functional theory calculations lead to the overestimated distances between base pairs, while MP2 computations and the newer complex functionals produce the structures that have too close atom-atom contacts. A detailed study of some complementary desoxydinucleoside monophosphate complexes with Na-ions highlights the existence of several energy minima corresponding to BI-conformations, in other words, the complexity of the relief pattern of the potential energy surface of complementary desoxydinucleoside monophosphate complexes. This accounts for variability of conformational parameters of duplex fragments with the same base sequence. Popular molecular mechanics force fields AMBER and CHARMM reproduce most of the conformational characteristics of desoxydinucleoside monophosphates and their complementary complexes with Na-ions but fail to reproduce some details of the dependence of the Watson-Crick duplex conformation on the nucleotide sequence.

LocalSCF method for semiempirical quantum-chemical calculation of ultralarge biomolecules.

A linear-scaling semiempirical method, LocalSCF, has been proposed for the quantum-chemical calculations of ultralarge molecular systems by treating the large-scale molecular task as a variational problem. The method resolves the self-consistent field task through the finite atomic expansion of weakly nonorthogonal localized molecular orbitals. The inverse overlap matrix arising from the nonorthogonality of the localized orbitals is approximated by preserving the first-order perturbation term and applying the second-order correction by means of a penalty function. This allows for the separation of the orbital expansion procedure from the self-consistent field optimization of linear coefficients, thereby maintaining the localized molecular orbital size unchanged during the refinement of linear coefficients. Orbital normalization is preserved analytically by the variation of virtual degrees of freedom, which are orthogonal to the initial orbitals. Optimization of linear coefficients of localized orbitals is performed by a gradient procedure. The computer program running on a commodity personal computer was applied to the GroEL-GroES chaperonin complex containing 119,273 atoms.

[Mechanisms of the changes in the rate and nature of reparative regeneration of the aortic endothelium after repeated injuries]. / Mekhanizmy izmenenii skorosti i kharaktera reparativnoi regeneratsii éndoteliia aorty pri mnogokratnykh povrezhdeniiakh.

An experimental model of repeated cryogenic lesions in the rat abdominal aorta endothelium with a concentrically decreasing area of the defect has been worked out. In reendothelization of every successive defect participate the cells of the endothelial layer that is formed anew after the preceding lesions. As a result of repeated lesions the regeneration rate increases by 1.2 times. By means of scanning radioautography after 3H-thymidine++ administration the index of the labelled nuclei of the endothelial cells (EC) has been demonstrated to increase by 2.2 times. In the experiments with gamma-irradiation of the vessel before the last cryodestruction (this results in blockade of proliferation) an increased rate of EC migration has been revealed. Repeated lesions also produce an increase in the heteromorphism degree of the endothelial layer. This is mainly manifested as appearance of multinuclear EC clusters. These changes in rate and in character of the endothelium regeneration can be determined by the mechanisms similar to clonal proliferative senescence of EC in vitro.

[The reparative regeneration of the endothelium of the mouse aorta during microsurgical interventions following local gamma irradiation (based on scanning electron microscopic data)]. / Reparativnaia regeneratsiia éndoteliia aorty krysy pri mikrokhirurgicheskikh vmeshatel'stvakh na fone lokal'nogo gamma-oblucheniia (po dannym skaniruiushchei élektronnoi mikroskopii.

In experiments with rats, abdominal aorta was subjected to microsurgical anastomosis after local irradiation with doses of 40 and 50 Gy. Irrespective of the time interval between the operation and irradiation the iatrogenic defect was restored completely. With the operation performed 24 h after irradiation the platelet adhesion decreased, the proliferation was inhibited depending on radiation dose, and the pattern of the endotheliocyte migration changed. The above effects were absent with the operation performed one month after irradiation.