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RNA polymerase II (POL II) is responsible for the transcription of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Previously, we have shown the evolutionary invariance of the structural features of DNA in the POL II core promoters of the precursors of mRNAs. In this work, we have analyzed the POL II core promoters of the precursors of lncRNAs in Homo sapiens and Mus musculus genomes. Structural analysis of nucleotide sequences in positions −50, +30 bp in relation to the TSS have shown the extremely heterogeneous 3D structure that includes two singular regions - hexanucleotide “INR” around the TSS and octanucleotide “TATA-box” at around ~−28 bp upstream. Thus, the 3D structure of core promoters of lncRNA resembles the architecture of the core promoters of mRNAs; however, textual analysis revealed differences between promoters of lncRNAs and promoters of mRNAs, which lies in their textual characteristics; namely, the informational entropy at each position of the nucleotide text of lncRNA core promoters (by the exception of singular regions) is significantly higher than that of the mRNA core promoters. Another distinguishing feature of lncRNA is the extremely rare occurrence in the TATA box of octanucleotides with the consensus sequence. These textual differences can significantly affect the efficiency of the transcription of lncRNAs.

Criteria for evaluating the conformational stability/lability of peptide fragments referred to fragments of protein structures are formulated. Using the proposed criteria, a statistical analysis of tetrapeptide fragments (their conformations and sequences) was performed in a sample of 25 121 protein chain structures from the PDB protein databank. As a result of the analysis, it was shown that tetrapeptide fragments significantly differ in the degree of the conformational stability/lability from the point of view of the proposed statistical criteria. The results of tetrapeptide denaturing molecular dynamics simulations were used as an independent approach to estimate the stability/lability of peptide fragments. A correlation between the estimates of conformational lability obtained on the basis of a statistical analysis of the ensembles of peptide conformations observed in experimentally determined protein structures and the estimates of conformational lability/stability calculated on the basis of molecular dynamics trajectories is demonstrated. Subgroups of more “conformationally stable peptides,” characterized mainly by the α-helical conformation, were obtained. Consensus tetrapeptides characterized by the lowest conformational lability (the highest conformational stability) were determined using complex criteria. Peptides with increased conformational lability were described. Thus, among all combinatorially possible tetrapeptides, the tetrapeptides that are characterized by certainty about their conformational state play a significant role. The relationship between the degree of conformational certainty of the peptide and its involvement in the primary structure of the protein was characterized. It was found that the role of the conformationally stable peptides in the formation of the protein structure was considerable, since they constitute, on average, approximately 10% of the amino-acid sequence. Using real soluble peptides as examples, the possibility of assessing the conformational stability of any preset amino-acid sequence on the basis of the developed criteria of the conformational lability of tetrapeptides was shown.

β-Bends are typical local structures of the polypeptide chain, are widespread in proteins, and play an important structural and functional role. It is possible to expect a priori with a good degree of certainty that β-bending structures are quite predictable; i.e., there are only a small number of β-bending conformations. Because a pseudo-cycle is closed through hydrogen bonding at the base of a β-bend, the number of independent parameters can be decreased to the extent such that a geometric analysis can be employed instead of a conformational analysis. As an example, a β-bending conformational set can be determined with high accuracy and reliability without using force fields. A conformational analysis of β-bends of the main types (I, I', II, and II') was performed using two independent methods, the original distance geometry procedure and the conformation enumeration procedure with subsequent optimization. A geometric analysis in the developed form was found to be sufficient for a conformational analysis of β-bends; i.e., the number of geometrically consistent β-bending conformations was reduced to two. The first solution found coincided with experimental data from X-ray structural analyses. The second solution was correct based on the geometric analysis, but was improbable in terms of energy because the corresponding values of the dihedral angles fell into strictly forbidden areas of the Ramachandran map as a result of disallowed convergence of atoms; the solution has not been observed experimentally. The results clarified the formation of the main β-bend conformation types, including those containing the so-called forbidden conformations.

MotivationLocal protein structure is usually described via classifying each peptide to a unique element from a set of pre-defined structures. These so-called structural alphabets may differ in the number of structures or the length of peptides. Most methods that predict the local structure of a protein from its sequence rely on this kind of classification. However, since all peptides assigned to the same class are indistinguishable, such an approach may not be sufficient to model protein folding with high accuracy.ResultsWe developed a method that predicts the structural representation of a peptide from its sequence. For 5-mer peptides, we achieved the Q16 classification accuracy of 67.9%, which is higher than what is currently reported in the literature. Importantly, our prediction method does not utilize information about protein homologues but only physicochemical properties of the amino acids and the statistics of the structures, but relies on a comprehensive feature-generation procedure based only on the protein sequence and the statistics of resolved structures. We also show that the 3D coordinates of a peptide can be uniquely recovered from its structural coordinates, and show the required conditions for that under various geometric constraints.AvailabilityThe online implementation of the method is provided freely at http://pbpred.eimb.ruContactmilch@eimb.ru or vmilchev@uni-koeln.deSupplementary informationSupplementary data are available online at http://pbpred.eimb.ru/S/index.html

An analog of the Ramachandran map was drawn, a new representation proposed, and thorough analysis performed using modern recognition and classification methods. Very large maps with a density of more than 50 million dots were created based on the data sets derived from the latest releases of globular protein- structure data banks. A, B, B', C, and D regions that correspond to strongly disallowed conformations were defined and found to occupy 25% of the plot area. A region of noncanonical conformations was determined by subtracting strongly disallowed and permitted conformation regions from the total plot area. Arguments are provided to support the new classification of backbone conformations of the protein polypeptide chain.

The interactions between protein and DNA in essence underlie all processes in a living cell. Understanding the principles of specific recognition of DNA sites will open the way to understand how these processes are controlled and to interfere in their operation. In the paper we studied contacts between the protein and DNA at the atomic level in the structures of all the 3 518 protein­DNA complexes available in PDB by the Voronoi–Delaunay tessellation method. The method unambiguously defines contacts between atoms without any parameters, and characterizes each contact by the distance between atoms and the contact area, which is determined by the corresponding face of the Voronoi polyhedron. It was shown that most contacts are formed between the protein atoms and the sugarphosphate backbone of the DNA (72.9 %). The contact with the atoms of the nucleic bases emerging into the grooves of DNA is 17.0 % for a major groove and 10.1 % for all atomic contacts for a minor groove. Totally, the interaction between protein atoms and nucleic base atoms accounts for 27.1 % of all contacts. Analysis of the accessible surface area of atoms in the major and the minor grooves showed a correlation with the number of contacts (coefficient of linear correlation 0.94 and 0.93, respectively), however, nucleic acid atoms forming hydrogen bonds make contacts more often than may be expected from statistical considerations. It was shown that conformationally stable peptides occur sometimes in the binding regions with DNA. Analysis of the residues in a predefined conformation in 3 518 protein­DNA complexes revealed 159 amino acid residues in a predefined β­bend type I conformation, 15 residues in the conformation of β­bend type I’, and 6 residues in the conformation of β­bend type II. No residues in the conformation of β­bend type II’ were found. Analysis of contacts showed that such residues virtually do not form contacts with DNA. Contacts with nucleic base atoms are found only in the two homologous structures 3qea and 3qe9, where threonine atoms form contacts with atoms of nucleotide bases of the AT­pair.

The dihedral angle ω, which reflects the nonplanarity of the peptide group, was found to be essential for describing the conformation of the polypeptide chain backbone in the context of particular side chain radicals of amino-acid residues. Conformational clusters corresponding to conformationally stable peptides identified previously were observed.

The fundamental criteria of the quality of molecular dynamics (MD) simulation represent a pivotal challenge, especially in the case of MD simulations of large systems (in particular, proteins).This work presents a simple theoretical analysis of time reversibility in classical mechanics that has allowed us to formulate a number of constructive criteria for evaluating the quality of the trajectories, generated in MD simulations. The results of testing the criteria on the structures of eight small proteins are presented. The criteria can be useful for solving different MD problems, such as: choosing the most appropriate thermostats for a MD system under study, the methods for sampling conformations, etc. Communicated by Ramaswamy H. Sarma

Left-handed helical conformation of a polypeptide chain (PPII) is the third type of the protein backbone structure. This conformation universally exists in fibrous, globular proteins, and biologically active peptides. It has unique physical and chemical properties determining a wide range of biological functions, from the protein folding to the tissue differentiation. New examples of the structure have been appearing in spite of difficulties in their detection and investigation. The annotation and prediction of the PPII was also a challenging task. Recently, many PPII motifs with new and/or unexpected functions are being accumulated in databases. In this review we describe the major structural and dynamic forms of PPII, the diversity of its functions, and the role in different biological processes.

A detailed analysis of polypeptide-chain backbone conformations was carried out for polypeptide-chain segments adjacent to β-turn regions, including the sites of disallowed conformations. A cross comparison of conformations was performed for disallowed regions of the Ramachandran plot and main types of β-turns and adjacent secondary structures. Based on the results, disallowed region 2 (II, II') in the Ramachandran plot was shown to coincide mainly with β-hairpins and, more exactly, twisted β-hairpins. The frequency of residues with angles ϕi, ψi that fall in region 2 (II, II') in the latter is 140 times higher than in common β-hairpins.

Efficient molecular recognition, in which recognition processes are occurring much faster than it takes to test variants, is only possible when long-distance recognition occurs together with contact interactions. The distance between interacting molecules should be sufficiently long to prevent hindrances to the search and, on the other hand, sufficiently short to provide selectivity. It was demonstrated that both of these two requirements can be satisfied simultaneously for biological macromolecules that include helical segments. Because the “diameters” of helical molecules are far shorter than their lengths, the intermolecular distance can be far greater than the diameters, thus allowing a free search. The distance can be far shorter than the lengths at the same time, thus providing selectivity. Analytical procedures were developed to estimate the parameters for protein–protein and protein–nucleic acid recognition. The coincidence of the charge-distribution periods in helical segments was found to substantially increase their interaction potential, and the reduction scale characteristic of the potential was shown to depend on the numerical value of the coinciding period.

The analysis of conformationally stable (conformational conservative) tetrapeptides selected from protein structures deposited in PDBSelect data bank has been fulfilled. The subset contained 943 tetrapeptide amino acid sequences and there were merely five 3D protein segment representatives for each sequence. As a result, the conclusion has been drawn on the basis of DSSP annotation analysis that in the majority of cases (900 of 943) alpha-helical conformation is obvious. Different than alpha-helix, in particular, the left-handed polyproline II helical conformation was observed in 43 sequences. The physical and chemical properties of conformationally stable peptides taken from the appropriate sample were estimated by the average hydrophobicity/hydrophilicity of tetrapeptides. The results of calculations show that the "neutrality" towards hydrophobicity/hydrophilicity is representative of conformationally stable oligopeptides. It should be noted, that dispersion of hydrophobicity/hydrophilicity distribution is sufficiently lower than for the test subsets. Thus, the conformationally stable oligopeptides present a distinct group of local protein structures which are very close with respect to conformational and physicochemical properties. In accordance with our developed theory of specific long range interactions these peptides are the objects being quite useful for effective mutual molecular recognition.

The work presents the results of an exhaustive conformational analysis of β-turns involving amino acid residues with disallowed backbone conformation of the polypeptide chain. It is known that the first residue of the β-turn (Asn47) of the distal β-hairpin in the α-spectrin SH3-domain is characterized by sterically disallowed main chain conformation (values of the dihedral angles (φ and ψ are in the right bottom quadrant of the Ramachandran plot). All α-spectrin structures with the anomalous elements deposited in the PDB were analysed. We hypothesized that the formation of disallowed conformation may occur through the fixation (due to the SH3 domain structure) of the adjacent to the β-turn amino acid residues with the β-structure. These residues are disposed in such a manner that β-turn conformation of the residues contributes just to the disallowed local conformation of this residue whereas any other β-turn conformations (with allowed local conformation) are impossible. To test this hypothesis an exhaustive conformational analysis of the β-bend has been performed by altering internal coordinates (two pairs of φ and ψ angles and two Ω angles). The conformations were selected as a result of grid search procedure with. 1 degrees step that corresponded to stereochemically allowed local deformations of the polypeptide chain segment forming the β-turn. In all conformations obtained the local conformation of Asn47 rests in the disallowed region. The conformations found include conformations coinciding with experimentally determined structures from the PDB as well as an additional variant that differs from X-ray structure in values of a pair of φ and ψ angles of the second residue belonging to the β-bend. Values of these angles fall in the region of the Ramachandran plot near the line φ = 0 (and negative values of ψ) i.e. in strongly disallowed region without experimental points. Therefore the additional variants of the β-turn local deformation are impossible to observe in experiment. Thus, the idea that disallowed conformation is intruded to the β-bend by fixation of adjacent residues receives confirmation in this work. The topological limitations in a context of the structure in such kind of β-hairpins exclude the allowed local conformations.

The structure of the SH3 domain of α-spectrin (PDB code 1SHG) features Asn47 in the II' area of the Ramachandran plot, which as a rule admits only glycine residues, and this phenomenon still awaits its explanation. Here, we undertook a computational study of this particular case by means of molecular dynamics and bioinformatics approaches. We found that the region of the SH3 domain in the vicinity of Asn47 remains relatively stable during denaturing molecular dynamics simulations of the entire domain and of its parts. This increased stability may be connected with the dynamic hydrogen bonding that is susceptible to targeted in silico mutations of Arg49. Bioinformatics analysis indicated that Asn47 is in the β-turn of a distinctive structural fragment we called 'alternatingly twisted β-hairpin.' Fragments of similar conformation are quite abundant in a nonredundant set of PDB chains and are distinguished from ordinary β-hairpins by some surplus of glycine in their β-turns, lack of certain interpeptide hydrogen bonds, and an increased chirality index. Thus, the disallowed conformation of residues other than glycine is realized in the β-turns of alternatingly twisted β-hairpins.

Methods based on the phenomenon of the specific long-range interaction between long macromolecules proposed for “speed reading” nucleotide sequences in single DNA molecules. One way is to measure the electric field potential along the preliminary stretched double DNA strand. Another way of information “reading” is to measure deformation of strand elements caused by an electric field that is generated by the “straightening” electrode due to an alternating voltage applied to it. On the base of the obtained information the sequence of nucleotides in the strand could be determined in principle.

Structures of many metal-binding proteins are often obtained without structural cations in their apoprotein forms. Missing cation coordinates are usually updated from structural templates constructed from many holoprotein structures. Such templates usually do not include structural water, the important contributor to the ion binding energy. Structural templates are also inconvenient for taking into account structural modifications around the binding site at apo-/holo- transitions. An approach based upon statistical potentials readily takes into account structural modifications associated with binding as well as contribution of structural water molecules. Here, we construct a set of statistical potentials for Mg2+, Ca2+, and Zn2+ contacting with protein atoms of a different type or structural water oxygens. Each type of the cations tends to form tight contacts with protein atoms of specific types. Structural water contributes relatively more into the binding pseudo-energy of Mg2+ and Ca2+ than of Zn2+. We have developed PIONCA (Protein-Ion Calculator), a fast CUDA GPGPU-based algorithm that predicts ion-binding sites in apoproteins. Comparative tests demonstrate that PIONCA outperforms most of the tools based on structural templates or docking. Our software can be also used for locating bound cations in holoprotein structures with missing cation heteroatoms. PIONCA is equipped with an interactive web interface based upon JSmol.

On the basis of the theory of specific long-range interaction between long molecules, an approach has been elaborated for «fast reading» of nucleotide sequences in one DNA molecule. First, a stretching force is applied to the molecule that causes its unwinding from B-form to S-form. Then, the molecule is placed in the stretched state on a support. After this, the electrostatic potential is estimated in a space along the DNA filament. The information obtained is sufficient for deducing the nucleotide sequence. Another approach to the «reading» of information reduces to measurement of the deformation of filament elements induced by the electric field from the electrode that stretches the filament by an alternating current applied.

For RNA-binding protein Pasilla, which has been shown to play a role in alternative splicing regulation, binding sites and clusters of binding sites are found in silico in the whole genome of D. melanogaster. The current study analyzes the occurrence of splice sites in binding site clusters. Several hundred thousand binding site motifs and thousands of significant motif clusters were identified. It was discovered that exonintron borders in D. melanogaster genes are reliably found within Pasilla binding motif clusters, with a higher frequency than could be otherwise expected based on a random model. Additionally, donor splice sites are found in Pasilla clusters twice as often as acceptor sites. This phenomenon is observed both for exons annotated as alternatively spliced and for exons annotated as constitutive. These observations support the hypothesis that Pasilla plays a functional role in splicing regulation of D. melanogaster.

We analyzed the periodic patterns in E. coli promoters and compared the distributions of the corresponding patterns in promoters and in the complete genome to elucidate their function. Except the three-base periodicity, coincident with that in the coding regions and growing stronger in the region downstream from the transcriptions start (TS), all other salient periodicities are peaked upstream of TS. We found that helical periodicities with the lengths about B-helix pitch ~10.2-10.5 bp and A-helix pitch ~10.8-11.1 bp coexist in the genomic sequences. We mapped the distributions of stretches with A-, B-, and Z- like DNA periodicities onto E.coli genome. All three periodicities tend to concentrate within non-coding regions when their intensity becomes stronger and prevail in the promoter sequences. The comparison with available experimental data indicates that promoters with the most pronounced periodicities may be related to the supercoiling-sensitive genes., 23 pages, 6 figures, 2 tables

The process of the globular structure formation from a long molecular chain is examined in a general sense. In the course of this process various regions of the chain interact with each other. The bonds formed during this process are classified as native and non-native ones. Native bonds are formed in native globular structure. All other bonds are “incorrect” (non-native). It is demonstrated that the globule formation can occur actually without production and subsequent decay of non-native contacts. The proposed model allows to avoid a search of numerous non-native variants since long-distance interactions with a high selectivity take place between the chain regions that form native bonds. The presence of these interactions prompts the chain regions which yield native contacts start to draw together and to interact. The databank data analysis shows that the developed model can be applied not only to the abstract structures but also to real polypeptide chains which are able to form both globular structures and helical fibrils.

We have suggested a method for magnetic sorting of cell suspensions capable of differentiating not only the cells with a single specific antigen on their surface, but also those with a group of given antigens. Individually, each antigen of this group could be present on the surfaces of undesired cells. However, only the simultaneous presence of all the given antigens on the cell surface indicates that such a cell should be separated. The method is of interest for purification of cell suspensions from malignant cells—in particular, for purification of bone marrow material for autologous transplantation in leukemia.

Fourier spectra of nucleotide sequences from chicken (Gallus gallus) chromosome 15 were obtained. Periodical structures of several fragments of the Ig light chain locus were characterized. The Fourier spectra of the locus and its parts (variable and constant segments, enhancer, and sequences supposedly associated with somatic hypermutation) were shown to be unique among those of other chromosome 15 fragments.

The distribution of secondary structure elements along the polypeptide chains of spider silk proteins spidroins 1 and 2 and their recombinant analogs has been studied by statistical methods. It was found that these proteins as monomers contain only traces of β-structure, while the Ala-rich and the Gly-rich regions are predicted as α-helices and as left-handed helices of polyproline II type. Analysis of literature and our CD data shows that the major polypeptide chain conformation of spidroins 1 and 2 and their recombinant analogs in aqueous solutions is the polyproline II helix, with some α-helices and a very small share of β-structures. The transition to the state with extended conformations, which are characteristic of mature silk fibers, requires dehydration of the polypeptide backbone. Thus, the genesis of β-structure in spider web proteins is determined by the conditions of transitions between the main regular backbone conformations.

Spider dragline silk possesses impressive mechanical and biochemical properties. It is synthesized by a couple of major ampullate glands in spiders and comprises of two major structural proteins--spidroins 1 and 2. The relationship between structure and mechanical properties of spider silk is not well understood. Here, we modeled the complete process of the spider silk assembly using two new recombinant analogs of spidroins 1 and 2. The artificial genes sequence of the hydrophobic core regions of spidroin 1 and 2 have been designed using computer analysis of existing databases and mathematical modeling. Both proteins were expressed in Pichia pastoris and purified using a cation exchange chromatography. Despite the absence of hydrophilic N- and C-termini, both purified proteins spontaneously formed the nanofibrils and round micelles of about 1 microm in aqueous solutions. The electron microscopy study has revealed the helical structure of a nanofibril with a repeating motif of 40 nm. Using the electrospinning, the thin films with an antiparallel beta-sheet structure were produced. In summary, we were able to obtain artificial structures with characteristics that are perspective for further biomedical applications, such as producing three-dimensional matrices for tissue engineering and drug delivery.

The structures of D-period segments of collagen (234 amino residues or ∼1/4 of whole length) are established by methods of molecular mechanics and geometry analysis. Each D-period segment proves to have a unique spatial structure. The distributions of local helical parameters along the molecule are calculated. It is found that a second hydrogen bond is formed in every case when the second residue in the tripeptide G-X-Y is an amino acid. With such a combined H-bond network, all the peptide CO groups of glycines and of the third residues in tripeptides have quasi-equivalent positions on the surface of the collagen molecule. The local deformations of the polyproline II helix in the triple complex give rise to the observed modulation of structure at the macromolecular level, which may be important for the mutual orientation of collagen molecules during fibrillogenesis.

In the previous paper in the series a full set of possible structures of double-helical DNA was obtained on the basis of complete scanning throughout conformational space of dihedral angles. In this work, these conformations have been used as starting points for energy optimization. All structures with Watson-Crick pairing coinciding with local minima of energy are deduced. These are right helices, B (a classical Wilkins B form), B1, B2 (the Watson and Crick form), B3, left helices, L1 (the Sasisekharan form), L2 (the Tumanyan et al. form), L3, and some helices without stacking of nucleotide pairs, K1-K6. Conformations B2, L2, and L1 are close to the B form with respect to energy (L3, B1, and B3 have rather poor energy). Incidentally, the similarity expands to values of helical parameters. For the structures described, the various energetic contributions in total energy have been estimated. The types of sugar conformations are analyzed. The possible biological significance of the elaborated optimal structures is discussed.

We describe a new method for polyproline II-type (PPII) secondary structure prediction based on tetrapeptide conformation properties using data obtained from all globular proteins in the Protein Data Bank (PDB). This is the first method for PPII prediction with a relatively high level of accuracy (approximately 60%). Our method uses only frequencies of different conformations among oligopeptides without any additional parameters. We also attempted to predict alpha-helices and beta-strands using the same approach. We find that the application of our method reveals interrelation between sequence and structure even for very short oligopeptides (tetrapeptides).

Van der Waals interaction energy in globular proteins is presented by the interaction energies between regions of protein spatial structure with homogenous medium density distribution. We introduce a notion of the local medium permittivity as a function of absorptance of molecular groups with particular conformation. Proposed theory avoids shortcomings which are typical for the calculations on the basis of the pairwise additive approximation. The approach takes into account local peculiarities of protein spatial structure and physical-chemical characteristics of amino acid residues and molecular groups.

Sequence weighting techniques are aimed at balancing redundant observed information from subsets of similar sequences in multiple alignments. Traditional approaches apply the same weight to all positions of a given sequence, hence equal efficiency of phylogenetic changes is assumed along the whole sequence. This restrictive assumption is not required for the new method PSIC (position-specific independent counts) described in this paper. The number of independent observations (counts) of an amino acid type at a given alignment position is calculated from the overall similarity of the sequences that share the amino acid type at this position with the help of statistical concepts. This approach allows the fast computation of position-specific sequence weights even for alignments containing hundreds of sequences. The PSIC approach has been applied to profile extraction and to the fold family assignment of protein sequences with known structures. Our method was shown to be very productive in finding distantly related sequences and more powerful than Hidden Markov Models or the profile methods in WiseTools and PSI-BLAST in many cases. The profile extraction routine is available on the WWW (http://www.bork.embl-heidelberg. de/PSIC or http://www.imb.ac.ru/PSIC).

Analysis of the structure of indels in algorithmic versus evolutionary alignments based on a set of inequalities confirms the conclusions from numerical modeling. For the more divergent sequences (PAM > 60), the tested aligning algorithm (SW) tends to increase the mean length of indels and decrease their number.

The data for 1109 protein-DNA complexes in PDB were analyzed for direct contacts between particular amino acid residues and nucleotides by rigorous space partitioning (Voronoi-Delaunay tessellation). When the actual occurrence of each kind of residue-nucleotide contact in the interface was related to its chance expectation, the most abundant contacts (made by Arg or Lys as well as by Ser or Thr) proved indiscriminate to heterocyclic bases, whereas a number of other, rarer contacts were clearly nonrandom, being significantly overrepresented or underrepresented in the sample of interfaces. Especially remarkable was the high overrepresentation of G/C contacts with negatively charged Asp/Glu. The nonrandom combinations showed no distinctions between purines and pyrimidines. This first step in formal analysis provides some hints concerning the accessibility of the “protein-DNA recognition code.”

The parametric description of residue environments through solvent accessibility, backbone conformation, or pairwise residue-residue distances is the key to the comparison between amino acid types at protein sequence positions and residue locations in structural templates (condition of protein sequence-structure match). For the first time, the research results presented in this study clarify and allow to quantify, on a rigorous statistical basis, to what extent the amino acid type-specific distributions of commonly used environment parameters are discriminative with respect to the 20 amino acid types. Relying on the Bahadur theory, we estimate the probability of error in a single-sequence-structure alignment based on weak or absent discriminative power in a learning database of protein structure. We present the results for many residue environment variables and demonstrate that each fold description parameter is sensitive with respect to only a few amino acid types while indifferent to most of the other amino acid types. Even complex structural characteristics combining solvent-accessible surface area, backbone conformation, and pairwise distances distinguish only some amino acid types, whereas the others remain nondiscriminated. We find that the knowledge-based potentials currently in use treat especially Ala, Asp, Gln, His, Ser, Thr, and Tyr as essentially "average" amino acids. Thus, highly discriminative amino acid types define the alignment register in gapless sequence-structure alignments. The introduction of gaps leads to alignment ambiguities at sequence positions occupied by nondiscriminated amino acid types. Therefore, local sequence-structure alignments produced by techniques with gaps cannot be reliable. Conceptionally new and more sensitive environment parameters must be invented.

We suggest a new simple approach for comparing the primary structure of proteins and their spatial structure. It relies on the one-to-one correspondence between each residue of the polypeptide chain and the energy of van der Waals interactions between the regions of the native globule flanking this residue. The method obviates the sophisticated geometrical criteria for estimating similarity between spatial structures. Besides, it permits one to analyze structural units of different scale.

It is well known, that local B→A transformation in DNA is involved in several biological processes. In vitro B↔A transition is sequence-specific. The physical basis of this specificity is not known yet. Here we analyze the effect of intramolecular interactions on the structural behavior of the GG/CC and AA/TT steps. These steps exemplify sequence specific bias to the B- or A-form structure. Optimization of potential energy of the molecular systems composed of an octanucle-otide, neutralized by Na(+) and solvated with TIP3P water molecules in rectangular box with periodic boundary conditions gives the statistically representative sets of low energy structures for GG/CC and AA/TT steps in the middle of the diverse flanking sequences. Permissible 3D variations of GG/CC and AA/TT, and correlation of the relative motion of base pairs in these steps were analyzed. AA/TT step permits high variability for low energy conformers in the B-form DNA and small variability for low energy conformers in the A-form DNA. In contrast GG/CC step permits high variability for low energy conformers in the A-form DNA and small variability for low energy conformers in the B-form DNA. The relative motion of base pairs in GG/CC step is high correlated, while in AA/TT step this correlation is notably less. Atom-atom interactions inside-the-step always favors the B-form and their component - stacking interactions (atomatom interactions between nucleic bases) is crucial for the duplex stabilization. Formation of the A-form for both steps is a result of interactions with the flanking sequences and water-cation environment in the box. The average energy difference between conformations presenting B-form and A-form for the GG/CC step is high, while for the AA/TT step it is rather low. Thus, intramolecular interactions in GG/CC and AA/TT steps affect the possible conformational diversity ("conformational entropy") of the A- and B- type structures of DNA step. This determines the known bias of the A-form DNA depending on the enrichment of sequences with GG/CC. If structural tuning during the process of protein-DNA complex formation lead to the local B→A transformation of DNA, it is largely directed by high conformational diversity of GG/CC step in the A-form. In such a case the presence in the target site of both kinds of examined steps ensures the reversible character of ligand binding.

Monte Carlo simulations [(N, V, T)-ensemble] were performed for the hydration shell of poly(dA-dT).poly(dA-dT) in canonical B form and for the hydration shell of poly(dA).poly(dT) in canonical B conformation and in a conformation with narrow minor groove, highly inclined bases, but with a nearly zero-inclined base pair plane (B' conformation). We introduced helical periodic boundary conditions with a rather small unit cell and a limited number of water molecules to reduce the dimensionality of the configuration space. The coordinates of local maxima of water density and the properties of one- and two-membered water bridges between polar groups of the DNA were obtained. The AT-alternating duplex hydration mirrors the dyad symmetry of polar group distribution. At the dApdT step, a water bridge between the two carbonyl oxygens O2 of thymines is formed as in the central base-pair step of Dickerson's dodecamer. In the major groove, 5-membered water chains along the tetranucleotide pattern d(TATA).d(TATA) are observed. The hydration geometry of poly(dA).poly(dT) in canonical B conformation is distinguished by autonomous primary hydration of the base-pair edges in both grooves. When this polymer adopts a conformation with highly inclined bases and narrow minor groove, the water density distribution in the minor groove is in excellent agreement with Dickerson's spine model. One local maximum per base pair of the first layer is located near the dyad axis between adjacent base pairs, and one local maximum per base pair in the second shell lies near the dyad axis of the base pair itself. The water bridge between the two strands formed within the first layer was observed with high probability. But the water molecules of the second layer do not have a statistically favored orientation necessary for bridging first layer waters. In the major groove, the hydration geometry of the (A.T) base-pair edge resembles the main features of the AT-pair hydration derived from other sequences for the canonical B form. The preference of the B' conformation for oligo(dA).oligo(dT) tracts may express the tendency to common hydration of base-pair edges of successive base pairs in the grooves of B-type DNA. The mean potential energy of hydration of canonical B-DNA was estimated to be -60 to -80 kJ/mole nucleotides in dependence on the (G.C) contents. Because of the small system size, this estimation is preliminary.

We calculated interchain contacts on the atomic level for nonredundant set of 4602 pro- tein-protein interfaces using an unbiased Voronoi- Delaune tessellation method, and made 20320 resi- due contact matrixes both for homodimers and heterocomplexes. The area of contacts and the dis- tance distribution for these contacts were calculated on both the residue and the atomic levels. We ana- lyzed residue area distribution and showed the exis- tence of two types of interresidue contacts: stochas- tic and specific. We also derived formulas describing the distribution of contact area for stochastic and specific interactions in parametric form. Maximum pairing preference index was found for Cys-Cys con- tacts and for oppositely charged interactions. A sig- nificant difference in residue contacts was observed between homodimers and heterocomplexes. Interfa- ces in homodimers were enriched with contacts between residues of the same type due to the effects of structure symmetry. Proteins 2007;67:1060-1077. V C 2007 Wiley-Liss, Inc.

In this paper we present a novel approach to membrane protein secondary structure prediction based on the statistical stepwise discriminant analysis method. A new aspect of our approach is the possibility to derive physical-chemical properties that may affect the formation of membrane protein secondary structure. The certain physical-chemical properties of protein chains can be used to clarify the formation of the secondary structure types under consideration. Another aspect of our approach is that the results of multiple sequence alignment, or the other kinds of sequence alignment, are not used in the frame of the method. Using our approach, we predicted the formation of three main secondary structure types (alpha-helix, beta-structure and coil) with high accuracy, that is Q(3) = 76%. Predicting the formation of alpha-helix and non-alpha-helix states we reached the accuracy which was measured as Q(2) = 86%. Also we have identified certain protein chain properties that affect the formation of membrane protein secondary structure. These protein properties include hydrophobic properties of amino acid residues, presence of Gly, Ala and Val amino acids, and the location of protein chain end.

A model for prediction of alpha-helical regions in amino acid sequences has been tested on the mainly-alpha protein structure class. The modeling represents the construction of a continuous hypothetical alpha-helical conformation for the whole protein chain, and was performed using molecular mechanics tools. The positive prediction of alpha-helical and non-alpha-helical pentapeptide fragments of the proteins is 79%. The model considers only local interactions in the polypeptide chain without the influence of the tertiary structure. It was shown that the local interaction defines the alpha-helical conformation for 85% of the native alpha-helical regions. The relative energy contributions to the energy of the model were analyzed with the finding that the van der Waals component determines the formation of alpha-helices. Hydrogen bonds remain at constant energy independently whether alpha-helix or non-alpha-helix occurs in the native protein, and do not determine the location of helical regions. In contrast to existing methods, this approach additionally permits the prediction of conformations of side chains. The model suggests the correct values for ~60% of all chi-angles of alpha-helical residues.

The purpose of the work was to investigate at the molecular structural and energy levels the consequence of amino acid substitutions in collagen that cause systemic diseases. The data have been systematized on defects in human collagen III, and the patterns of single-nucleotide polymorphisms collected. Then molecular mechanics calculations were performed for native and mutant collagen molecule fragments. The observed energy components and structural alterations that accompany particular amino acid substitutions were used to propose an interpretation of negative consequences in terms of stability and hydration of the macromolecule.

An algorithm for determining of protein domain structure is proposed. Domain structures resulted from the algorithm application have been obtained and compared with available data. The method is based on entirely physical model of van der Waals interactions that reflects as illustrated in this work the distribution of electron density. Various levels of hierarchy in the protein spatial structure are discerned by analysis of the energy interaction between structural units of different scales. Thus the level of energy hierarchy plays role of sole parameter, and the method obviates the use of complicated geometrical criteria with numerous fitting parameters. The algorithm readily and accurately locates domains formed by continuous segments of the protein chain as well as those comprising non-sequential segments, sets no limit to the number of segments in a domain. We have analyzed 309 protein structures. Among 277 structures for which our results could be compared with the domain definitions made in other works, 243 showed complete or partial coincidence, and only in 34 cases the domain structures proved substantially different. The domains delineated with our approach may coincide with reference definition at different levels of the globule hierarchy. Along with defining the domain structure, our approach allows one to consider the protein spatial structure in terms of the spatial distribution of the interaction energy in order to establish the correspondence between the hierarchy of energy distribution and the hierarchy of structural elements.