Biomedical subjects

A A Gorin

Publications and source records attributed to A A Gorin.

12 recordsLinked to original sources

PubMed1998

DNA sequence-dependent deformability deduced from protein-DNA crystal complexes.

The deformability of double helical DNA is critical for its packaging in the cell, recognition by other molecules, and transient opening during biochemically important processes. Here, a complete set of sequence-dependent empirical energy functions suitable for describing such behavior is extracted from the fluctuations and correlations of structural parameters in DNA-protein crystal complexes. These elastic functions provide useful stereochemical measures of the local base step movements operative in sequence-specific recognition and protein-induced deformations. In particular, the pyrimidine-purine dimers stand out as the most variable steps in the DNA-protein complexes, apparently acting as flexible "hinges" fitting the duplex to the protein surface. In addition to the angular parameters widely used to describe DNA deformations (i.e., the bend and twist angles), the translational parameters describing the displacements of base pairs along and across the helical axis are analyzed. The observed correlations of base pair bending and shearing motions are important for nonplanar folding of DNA in nucleosomes and other nucleoprotein complexes. The knowledge-based energies also offer realistic three-dimensional models for the study of long DNA polymers at the global level, incorporating structural features beyond the scope of conventional elastic rod treatments and adding a new dimension to literal analyses of genomic sequences.

DNA↗

PubMed1997

Architectural accommodation in the complex of four p53 DNA binding domain peptides with the p21/waf1/cip1 DNA response element.

High resolution chemical footprinting and cross-linking experiments have provided a basis for elucidating the overall architecture of the complex between the core DNA binding domain of p53 (p53DBD, amino acids 98-309) and the p21/waf1/cip1 DNA response element implicated in the G1/S phase cell cycle checkpoint. These studies complement both a crystal structure and earlier biophysical studies and provide the first direct experimental evidence that four subunits of p53DBD bind to the response element in a regular staggered array having pseudodyad symmetry. The invariant guanosines in the highly conserved C(A/T)|(T/A)G parts of the consensus half-sites are critical to the p53DBD-DNA binding. Molecular modeling of the complex using the observed peptide-DNA contacts shows that when four subunits of p53DBD bind the response element, the DNA has to bend approximately 50 degrees to relieve steric clashes among different subunits, consistent with recent DNA cyclization studies. The overall lateral arrangement of the four p53 subunits with respect to the DNA loop comprises a novel nucleoprotein assembly that has not been reported previously in other complexes. We suggest that this kind of nucleoprotein superstructure may be important for p53 binding to response elements packed in chromatin and for subsequent transactivation of p53-mediated genes.

Base Sequence↗

PubMed1997

Individual differences in the diurnal cycle of cortisol.

This study investigated individual differences in the diurnal cycle of cortisol and explored their relation to several psychosocial variables and to upper-respiratory symptoms. Cortisol and daily experience were assessed for 2 days in 109 healthy employed and unemployed community residents (mean age = 36.4 +/- 12.1, 69% female); self-report upper respiratory illness (URI) symptoms were assessed for an additional 10 days. Fifty-six (51%) participants showed typical declines in cortisol during both days, 19 (17%) showed no significant diurnal pattern on both days, and 34 (31%) showed different diurnal patterns on the 2 days. Individuals with no cycles did not differ from those with normal or inconsistent cycles on demographic factors, baseline psychological measures, health behaviors, or daily experiences over the two assessment days. Individuals without cortisol cycles, however, reported fewer URI symptoms than the remaining subjects. That 17% of our sample did not exhibit diurnal cycles of cortisol was surprising, given established views of normal endocrine function. Although average daily level of cortisol is related to a number of psychosocial and psychiatric factors (e.g. stress and depression), pattern of diurnal cycle was not related to any demographic or psychosocial measures in this study. The finding that flat cycles were related to fewer reports of URI symptoms suggests that perturbations in cycle may be related to processes associated with symptom susceptibility or symptom expression.

Adult↗

PubMed1997

Three-dimensional model for slipped loop RNA.

Earlier a three-dimensional model for a new unusual DNA conformation referred to as Slipped Loop Structure (SLS) has been suggested by us (1). The same type of folding could occur with RNA as well which means that one must use the A-form of the double helix rather than the B-one. The present paper discusses the creation of an all-atom stereochemically sound model for SLS-RNA. This calculated model, while possessing the same folding topology as the SLS-DNA, differs dramatically from the SLS-DNA by an overall folding geometry. It also differs radically from the RNA-pseudoknot and can thus be regarded as a new type of an RNA folding.

Base Sequence↗

PubMed1995

B-DNA twisting correlates with base-pair morphology.

The observed sequence dependence of the mean twist angles in 38 B-DNA crystal structures can be understood in terms of simple geometrical features of the constituent base-pairs. Structures with low twist appear to unwind in response to severe steric clashes of large exocyclic groups (such as NH2-NH2) in the major and minor grooves, while those with high twist are subjected to lesser contacts (H-O and H-H). We offer a simple clash function that depends on base-pair morphology (i.e. the chemical constitution of base-pairs) and satisfactorily accounts for the twist angles of the ten common Watson-Crick dimer steps both in the solid state and in solution. The twist-clash correlation that we find here still holds when extended to modified bases. In addition to Calladine's purine-purine clashes, we add other close contacts between bases in the grooves, and consider the conformational restrictions on the geometry of the sugar-phosphate backbone (namely, we emphasize the tendency of DNA to conserve virtual backbone length). The significance of this finding is threefold: (1) sequence-dependent DNA twisting is directly involved in protein-DNA interactions; (2) strong correlation between Twist and Roll helps to elucidate the bending of the double helix as a function of base sequence; (3) it is possible to anticipate the effects of chemical modifications on twisting and bending. The mutual correlations of other structural parameters with the twist make this angle a primary determinant of DNA conformational heterogeneity.

Base Sequence↗

PubMed1992

Systematic study of nuclear Overhauser effects vis-à-vis local helical parameters, sugar puckers, and glycosidic torsions in B DNA: insensitivity of NOE to local transitions in B DNA oligonucleotides due to internal structural compensations.

A method has been developed to solve structures of DNA oligomers in solution from the experimental NOE data. The method is a combination of two approaches: (1) full matrix NOESY simulations and (2) conformational calculations of DNA double helix based on generalized helical parameters. The process of the refinement of a solution structure does not involve NMR-derived interproton distance constraints; rather it consists of a direct fitting of a structure to the experimental NOE data, a weighted sum of energy, and R factor being under minimization. A helical parameters-based generation of DNA forms makes it possible to organize the search for the optimal structure more effectively, systematically varying starting conformations. The method has been used to calculate a structure for the self-complementary DNA hexamer GGATCC, which is consistent with the available experimental data. The structure belongs to the B family of forms, although the local structural heterogeneity is very strong. Sugar puckers vary from O4'-exo to C3'-exo; helical steps are open with different magnitudes toward the minor groove. Next, we have addressed the question of how uniquely the structure is defined by the existing NMR data. Different structural parameters have been systematically varied, and their effect on individual NOE's and the R factor has been studied. Two energetically conjugated parameters, sugar puckers and glycosidic angles, can be determined very reliably, because of the strong dependences of the intraresidue H6/H8 to H2'/H2''/H3' NOE's. In contrast, the local helical conformation of DNA and the geometry of base pairs proved to be underdetermined by the existing NOE information, because the effect of any helical parameter on interproton distances can be compensated by the concerted changes in other parameters.

Base Composition↗

PubMed1991

Static and statistical bending of DNA evaluated by Monte Carlo simulations.

To investigate the influence of thermal fluctuations on DNA curvature the Metropolis procedure at 300 K was applied to B-DNA decamers containing A5.T5 and A4.T4 blocks. Monte Carlo simulations have confirmed the DNA bending anisotropy: B-DNA bends most easily in a groove direction (roll). The A5.T5 block is more rigid than the other sequences; the pyrimidine-purine dimers are found to be the most flexible. For A5TCTCT, A5CTCTC, and A5GAGAG, the average bend angle per decamer is 20-25 degrees in a direction toward the minor groove in the center of the A5.T5 tract, which is consistent with both the "junction" and "wedge AA" models. However, in A5T5, A4T4CG, and T4A4GC, bending is directed into the grooves at the 5' and 3' ends of purine tracts. Thus, directionality of bending caused by An.Tn blocks strongly depends on their neighboring sequences. These calculations demonstrate that the sequence-dependent variation of the minor-groove width mimics the observed hydroxyl radical cleavage pattern. To estimate the effect of fluctuations on the overall shape of curved DNA fragments, longer pieces of DNA (up to 200 base pairs) were generated. For sequences with strong curvature (A5X5 and A4T4CG), the static model and Monte Carlo ensemble give similar results but, for moderately and slightly curved sequences (A5T5 or T4A4GC), the static model predicts a much smaller degree of bending than does the statistical representation. Considering fluctuations is important for quantitative interpretation of the gel electrophoresis measurements of DNA curvature, where both the static and statistical bends are operative.

Base Sequence↗

PubMedDate not supplied

[Structure of d(GT)n repeating sequences with parallel and antiparallel chains].

The ability of oligonucleotides 3'-d(GT)5pO(CH2)5Opd(GT)5-5' (anti[d(GT)]) and 3'-d(GT)5pO(CH2)6Opd(GT)5-3' (par[d(GT)]) to form hairpins and higher associates is studied. Optical methods of thermal denaturation and circular dichroism as well as the fluorescence of ethidium bromide and acridine orange bound to oligonucleotides were used. At room temperatures the formation of hairpin structure with parallel and antiparallel strands is possible. Thermodynamic parameters of par[d(GT)] and anti[d(GT)] are similar and equal to delta H = -15 kcal/mol, delta S = -50 cal/mol. deg. In the temperature range 3-10 degrees C par[d(GT)] and anti[d(GT)] form four-stranded structures with parallel chains, in which layers of four G-residues alternate with unpaired T-residues being bulged out easily. On comparison of occurrence of alternating (GT)n, (GC)n and (G)n sequences in genome it can be stated that (GT)n biological functions could be connected with conformational possibilities of the four-stranded parallel structures with unpaired T-residues.

Circular Dichroism↗

PubMedDate not supplied

[SLS--a new type of polynucleotide chain folding].

Short tandem repeats (5-8 base pairs) are not uncommon in the prokaryotic and eukaryotic DNA. Regions with such sequence motifs, when under superhelical stress, manifest unusual sensitivity to single-strand specific nuclease. To explain this, it has been suggested that one DNA thread should be shifted relatively to another, so that they could form two single-stranded loops protruding from the opposite chains and separated on the DNA helix by the length of a direct repeat. The structure was proposed to play a role in the regulation of transcription, organization of chromatin and in the recombination. Such type of folding could have been extra-stabilized by base pairing between the loops. This attractive possibility of the interloop minihelix formation requires a delicate stereochemical analysis and direct experimental support. Formation of the interloop minihelix in the Slipped Loop Structure (SLS) was tested by a chemical modification method at one nucleotide level resolution. The results show that bases located within the proposed interloop helix are well protected from the probes used. This fact encourages us to publish a 3-D model for the SLS-form DNA (and RNA). The SLS is characterized by a remarkable symmetry having three mutually perpendicular dyad axes. Scanning the bank of nucleotide sequences has revealed more than 500 sites, the transcripts of which are capable of folding into the SLS form, which allow us to regard the SLS form as a novel universal structural form. Remarkably, the abundance of SLS in intrones three times exceeds that of the coding sequences. This may reflect a functional role (or roles) of the SLS conformation.

Animals↗

PubMedDate not supplied

[Parallel DNA helices. Conformational analysis of regular poly(dG).poly(dC) helices with different variants of base binding].

We have performed a conformational analysis of DNA double helices with parallel directed backbone strands. The calculations were made for homopolymers poly(dG).poly(dC). All possible models of base binding were checked. By the potential energy optimization the dihedral angles and helices parameters of stable conformations of parallel double polynucleotides were calculated. The dependences of conformational energy on the base pair structure were studied. Possible structure of parallel helices with various nucleotide composition are discussed.

DNA↗

PubMedDate not supplied

[S-N transition of the saccharide ring in B-form DNA].

A conformational transition of a single deoxyribose was analyzed in B-form trimers dA3:dT3 and dG3:dC3, both in the purine and pyrimidine chains. The main results were obtained for the duplexes with frozen ends, which could be extended by regular double helixes. The geometry of the central sugar ring in the duplexes may strongly deviate from the regular conformation. When deoxyribose changed its conformation in the central pyrimidine, the energy increase was proved to be less significant in comparison with that for purine. In the case of Thy, a decrease in pseudorotation angle P from 140 to 80 degrees causes the energy increase of 0.5 kcal/mol only, the barrier being 1.2 kcal/mol. The energy profile for Cyt has several local minima. The results of calculations were compared with numerous experimental data, they help to explain some NMR data. A perturbation of the duplex AAA:TTT structure caused by the thymine sugar ring transition, produces 5 degrees bend of the DNA axis directed toward adenines. We also investigated the influence of such conformational disturbance on the neighbouring base pairs, in particular the transition in the trimers with unfrozen ends.

DNA↗

PubMedDate not supplied

[A compressed form for presenting data to banks on the primary and spatial structure of biopolymers. Means for accessing compressed data banks].

Description of open CAN format (Compressed Amino acids and Nucleotides) is presented for storing genetic information in compressed form in data banks (DB). Data compression principles are demonstrated in detail on examples of EMBL DB (sequences of nucleotides), SWISSPROT DB (sequences of amino acids) and PDB DB (3D structures). A unified compressed data format provides a possibility to integrate EMBL, SWISSPROT, and PDB DB in one data bank. We are going to use this approach for integration of GENBANK and other similar DBs. One of the outcomes of the research is a library of data retrieval procedures for access to DB, providing developers of the application software packages with a uniform interface to DBs with biologically related data. The proposed scheme for data representation was recommended by the Expert Commission of the Informatics Section of the RSSIP "Human Genome" as a standard for distribution of data banks in Russia.

Amino Acid Sequence↗