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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.

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.

Motivation: Local protein structure is usually described via classifying each peptide to a unique class from a set of pre-defined structures. These classifications may differ in the number of structural classes, the length of peptides, or class attribution criteria. Most methods that predict the local structure of a protein from its sequence first rely on some classification and only then proceed to the 3D conformation assessment. However, most classification methods rely on homologous proteins' existence, unavoidably lose information by attributing a peptide to a single class or suffer from a suboptimal choice of the representative classes., Results: To alleviate the above challenges, we propose a method that constructs a peptide's structural representation from the sequence, reflecting its similarity to several basic representative structures. For 5-mer peptides and 16 representative structures, we achieved the Q16 classification accuracy of 67.9%, which is higher than what is currently reported in the literature. Our prediction method does not utilize information about protein homologues but relies only on the amino acids' physicochemical properties and the resolved structures' statistics. We also show that the 3D coordinates of a peptide can be uniquely recovered from its structural coordinates, and show the required conditions under various geometric constraints., Competing Interests: The authors have declared that no competing interests exist.

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 Mg 2+ , Ca 2+ , and Zn 2+ 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 Mg 2+ and Ca 2+ than of Zn 2+ . 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.

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.

The level of supercoiling in the chromosome can affect gene expression. To clarify the basis of supercoiling sensitivity, we analyzed the structural features of nucleotide sequences in the vicinity of promoters for the genes with expression enhanced and decreased in response to loss of chromosomal supercoiling in Escherichia coli. Fourier analysis of promoter sequences for supercoiling-sensitive genes reveals the tendency in selection of sequences with helical periodicities close to 10nt for relaxation-induced genes and to 11nt for relaxation-repressed genes. The helical periodicities in the subsets of promoters recognized by RNA polymerase with different sigma factors were also studied. A special procedure was developed for the study of correlations between the intensities of periodicities in promoter sequences and the expression levels of corresponding genes. Significant correlations of expression with the AT content and with AT periodicities about 10, 11, and 50nt indicate their role in regulation of supercoiling-sensitive genes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Algorithms of sequence alignment are the key instruments for computer-assisted studies of biopolymers. Obviously, it is important to take into account the "quality" of the obtained alignments, i.e. how closely the algorithms manage to restore the "gold standard" alignment (GS-alignment), which superimposes positions originating from the same position in the common ancestor of the compared sequences. As an approximation of the GS-alignment, a 3D-alignment is commonly used not quite reasonably. Among the currently used algorithms of a pair-wise alignment, the best quality is achieved by using the algorithm of optimal alignment based on affine penalties for deletions (the Smith-Waterman algorithm). Nevertheless, the expedience of using local or global versions of the algorithm has not been studied., Results: Using model series of amino acid sequence pairs, we studied the relative "quality" of results produced by local and global alignments versus (1) the relative length of similar parts of the sequences (their "cores") and their nonhomologous parts, and (2) relative positions of the core regions in the compared sequences. We obtained numerical values of the average quality (measured as accuracy and confidence) of the global alignment method and the local alignment method for evolutionary distances between homologous sequence parts from 30 to 240 PAM and for the core length making from 10% to 70% of the total length of the sequences for all possible positions of homologous sequence parts relative to the centers of the sequences., Conclusion: We revealed criteria allowing to specify conditions of preferred applicability for the local and the global alignment algorithms depending on positions and relative lengths of the cores and nonhomologous parts of the sequences to be aligned. It was demonstrated that when the core part of one sequence was positioned above the core of the other sequence, the global algorithm was more stable at longer evolutionary distances and larger nonhomologous parts than the local algorithm. On the contrary, when the cores were positioned asymmetrically, the local algorithm was more stable at longer evolutionary distances and larger nonhomologous parts than the global algorithm. This opens a possibility for creation of a combined method allowing generation of more accurate alignments.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Abstract 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.

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 octanucleotide, 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 (atom-atom 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.

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.

In many applications, the algorithmically obtained alignment ideally should restore the "golden standard" (GS) alignment, which superimposes positions originating from the same position of the common ancestor of the compared sequences. The average similarity between the algorithmically obtained and GS alignments ("the quality") is an important characteristic of an alignment algorithm. We proposed to determine the quality of an algorithm, using sequences that were artificially generated in accordance with an appropriate evolution model; the approach was applied to the global version of the Smith-Waterman algorithm (SWA). The quality of SWA is between 97% (for a PAM distance of 60) and 70% (for a PAM distance of 300). The percentage of identical aligned residues is the same for algorithmic and GS alignments. The total length of indels in algorithmic alignments is less than in the GS-mainly due to a substantial decrease in the number of indels in algorithmic alignments.

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.

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)., (Proteins 2005. 2005 Wiley-Liss, Inc.)

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.

A new approach to predicting protein standard conformations is suggested. The idea consists in modeling by molecular mechanics tools a continuous alpha-helical conformation for the whole protein. The profile of energy along the model alpha-helix reveals minima corresponding to real alpha-helical segments in the native protein. The 3/10-helices and beta-turns including a local alpha-helical conformation may be detected as well. All alpha-helical segments in the test sample are delineated; mean residue by residue accuracy Q(3alpha) is 79%. This non-statistical approach can shed light on the physical grounds of alpha-helix formation.

Unlabelled: We present a software system BASIO that allows one to segment a sequence into regions with homogeneous nucleotide composition at a desired length scale. The system can work with arbitrary alphabet and therefore can be applied to various (e.g. protein) sequences. Several sequences of complete genomes of eukaryotes are used to demonstrate the efficiency of the software., Availability: The BASIO suite is available for non-commercial users free of charge as a set of executables and accompanying segmentation scenarios from http://www.imb.ac.ru/compbio/basio. To obtain the source code, contact the authors.

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.

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.

We present a new approach to DNA segmentation into compositionally homogeneous blocks. The Bayesian estimator, which is applicable for both short and long segments, is used to obtain the measure of homogeneity. An exact optimal segmentation is found via the dynamic programming technique. After completion of the segmentation procedure, the sequence composition on different scales can be analyzed with filtration of boundaries via the partition function approach.

The method of the representation of amino acid sequence by graph of the interactions energy between parts of spatial structure has been elaborated. Our method provides the possibility to establish the compatibility between each point of a polypeptide chain and the Van der Waals interactions energy of regions of a native globule adjacent to this amino acid residue. We have undertaken an exhaustive analysis of a set of proteins. Boundaries of domain and module structures have been found. Nonequivalence of different parts of sequences in respect to their contribution to stabilization of the spatial structure of the protein macromolecules has been revealed. On the basis of the number of energetic levels which are necessary to identify all independent parts of the globule, the contribution from each part of the sequence to stabilization of the spatial structure of the globule is defined. Thus, it has been found that the sequence of amino acid residues coincides with the sequence of the numerical values which can be used in turn in formal procedures, such as an alignment, a search of consensus, the recognition of composition peculiarities, etc. An example of the comparison of proteins with various sequence identities is considered to demonstrate the scheme of an alignment procedure.

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.

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).

This paper concerns the conformational variability of collagen as related to the concrete tripeptides (GXY)n constituting its primary structure. The previously elaborated model (V.G.Tumanyan, N.G.Esipova, Biophysics 28, 1021-1025, 1983) with two nets of hydrogen bonds is useful for tripeptides where X is an amino acid. If X is an imino acid, the common one-bonded Rich & Crick model is valid. In this work, compound sequences including tripeptides of different types are considered. Molecular mechanics is used to assess the conformations of the junction regions when a structure with two nets of hydrogen bonds precedes the structure with one net, and vice versa. Thus, all types of sequences typical for natural collagen are covered. It is shown that the combined model representing an alternation of the two-H-bonded model and the one-H-bonded Rich & Crick model is satisfactory stereochemically, and provides more favorable energy in comparison with the continuous one-H-bonded model. Besides, a more favorable hydration of the molecule occures in this case. Some conclusions are made about interchain and intrachain ionic bonds. Thus, it is deduced for the concrete fibrillar protein how a one-dimensional structure determines three-dimensional structure. The macromolecular structure thus suggested is in accord with the experimental data on hydrogen exchange.

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.

We have undertaken an exhaustive statistical analysis of the amino acid sequences at the carboxyl-terminal (C) ends of proteins. The composition of the C-terminal decapeptides differs from that expected for the given proteins from the overall amino acid composition. For E. coli, yeast, and H. sapiens it was shown that positively charged amino acid residues are over-represented while Gly residues are under-represented. The C-terminal bias, a novel feature of protein structure, should be taken into account when molecular evolution, spatial structure, translational termination and protein folding are concerned.

We discuss a new convenient way to study periodical patterns in primary structures of biopolymers which appeared recently. For the sequence of a biopolymer the symbolic correlation function is constructed, which is used as a digital sequence thus allowing us to perform a Fourier transform. Another fruitful technical improvement is the closing of the sequence in the ring with further scanning of the ring length, which allows the study of periods of the order of the sequence length. This approach makes it possible to take into account any scores describing similarity between symbols and to compare results obtained using different Fourier-like and correlation matrix techniques. An algorithm to compute Fourier spectrum power allows detection of vague periods in sequences containing strong repeats. A PASCAL program, SYMFOUR, has been written and tested on both sequences with periodical patterns, already reported, and sequences and other sites interesting from a biological point of view.

Collagen is a fibrous protein with a primary structure with complex periodical features. We show using symbolic Fourier transform of the collagen cDNA sequence that basic periodical patterns appear there also. Strikingly they are present in the third position of triplets encoding Gly, which occupies each third position in the sequence of the protein, and to which selection on the protein level does not applied. Thus, the gene of collagen seems to appear due to pra-gene multiplication.

Being interested in possible effects of sequence-dependent hydration of B-DNA with mixed sequence in fibers, we performed a series of Monte Carlo calculations of hydration of polydeoxyribonucleotides in B form, considering all sequences with dinucleotide repeat. The computational results allow the ten base-stacking types to be classified in accordance with their primary hydration in the minor groove. As a rule, the minor groove is occupied by two water molecules per base pair in the depth of the groove, which are located nearly midway between the planes of successive base pairs and symmetrically according to the dyad there. The primary hydration of the major groove depends on the type of the given base pair. The coordinates of 3 water molecules per base pair in the depth of the major groove are determined by the type of this pair together with its position and orientation in the helix, and are practically independent on the adjacent base pairs. A/T-homopolymer tracts do not fit into this hydration pattern; the base pair edges are hydrated autonomously in both grooves. Analysis of the Li-B-DNA x-ray diffraction intensities reveals those two water positions in the minor groove. In the major groove, no electronic density peaks in sufficient distance from the base edges were found, thus confirming the absence of any helical invariance of primary hydration in this region. With the help of the rules proposed in this paper it is possible to position the water molecules of the first hydration shell in the grooves of canonical B-DNA for any given sequence.

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.

A model is suggested for the lac repressor binding to the lac operator in which the repressor polypeptide chain sequences from Gly 14 to Ala 32 and from Ala 53 to Leu 71 are involved in specific interaction with operator DNA. A correspondence between the protein and DNA sequences is found which explains specificity of the repressor binding to the lac operator. The model can be extended to describe specific binding of other regulatory proteins to DNA.

A complete classification of types of the protein secondary structure is developed on the basis of computer analysis of the crystallographic structural data deposited in the protein Data Bank. The majority of amino acid residues fall into five conformation types. A conclusion is drawn that the number of sequence variants of torsion angles phi, psi in globular proteins is limited and is essentially less than the number of possible amino acid sequences for this chain length. Along with alpha-helix and beta-structure, the distribution analysis assigning every maximum of distribution of amino acid conformations on Ramachandran map to a certain type of the secondary structure exposed a third type of the secondary structure that was previously neglected. This type of the structure is extended left-handed helical conformation, designated as mobile (M-) conformation. A full set of M-conformation fragments that seems to play a major role in protein globule dynamics has been obtained, a small radius of correlation for the polypeptide chain in M-conformation is demonstrated. It explains a prevalence of short segments of mobile conformation revealed in globular proteins. For secondary structure types, the frequency of occurrence of amino acid residues has been computed.

A computational method is elaborated for studying the water environment around regular polynucleotide duplexes; it allows rigorous structural information on the hydration shell of DNA to be obtained. The crucial aspect of this Monte Carlo simulation is the use of periodical boundary conditions. The output data consists of local maxima of water density in the space near the DNA molecule and the properties of one- and two-membered water bridges as function of pairs of polar groups of DNA. In the present paper the results for poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) are presented. The differences in their hydration shells are of a purely structural nature and are caused by the symmetry of the polar groups of the polymers under study, the symmetry being reflected by the hydration shell. The homopolymer duplex hydration shell mirrors the mononucleotide repeat. The water molecules contacting the polynucleotide in the minor groove are located nearly in the plane midway between the planes of successive base pairs. One water molecule per base pair forms a water bridge facing two polar groups of bases from adjacent base pairs and on different strands making a "spine"-like structure. In contrast, the major groove hydration is stabilized exclusively by two-membered water bridges; the water molecules deepest in the groove are concentrated near the plane of the corresponding base pair. The alternating polymer is characterized by a marked dyad symmetry of the hydration shell corresponding to the axis between two successive base pairs. The minor groove hydration of the dCpdG step resembles the characteristic features of the homopolymer, but the bridge between the O2 oxygens of the other base-stacking type is formed by two water molecules. The major groove hydration is characterized by high probability of one-membered water bridges and by localization of a water molecule on the dyad axis of the dGpdC step. The found structural elements are discussed as reasonable invariants of a dynamic hydration shell.

Analysis of 68 proteins from Protein Data Bank disclosed a new widely spread type of the secondary structure that is designated as mobile (M-) conformation. Helical parameters of M-conformation are close to the poly-L-proline II type helix. Its occurrence in globular proteins approximates that of the beta-sheet. The angles corresponding to the position of the M-conformation maximum in distribution of amino acid residues on a conformational map are phi: -65 degrees, psi: 140 degrees. Unique features and high occurrence in proteins make it possible to distinguish the M-conformation as an independent third type of the secondary structure in globular proteins, that should be included in the present classification.

A possible code is suggested that describes a correspondence between amino acid sequences in stereospecific sites of regulatory proteins and nucleotide sequences at the control sites on DNA. Stereospecific sites of regulatory proteins are assumed to contain pairs of antiparallel polypeptide chain segments which form a right-hand twisted antiparallel beta-sheet with single-stranded regions at the ends of the beta-structure. The binding reaction between regulatory protein and double-helical DNA is accompanied by significant structural alterations at stereospecific sites of the protein and DNA. Half of the hydrogen bonds normally existing in beta-structure are broken upon complex formation with DNA and a new set of hydrogen bonds is formed between polypeptide amide groups and DNA base pairs. The code states a correspondence between four amino acid residues at a stereospecific site of the regulatory protein and an AT (GC) base pair at the control site. It predicts that there are six fundamental amino acid residues (serine, threonine, histidine, asparagine, glutamine and cysteine) whose arrangement in the stereospecific site determines the base pair sequence to which a given regulatory protein would bind preferentially.