MOTIVATION: Interchain beta-sheet (ICBS) interactions occur widely in protein quaternary structures, interactions between proteins and protein aggregation. These interactions play a central role in many biological processes and in diseases ranging from AIDS and cancer to anthrax and Alzheimer's. RESULTS: We have created a comprehensive database of ICBS interactions that is updated on a weekly basis and allows entries to be sorted and searched by relevance and other criteria through a simple Web interface. We derive a simple ICBS index to quantify the relative contributions of the beta-ladders in the overall interchain interaction and compute first- and second-order statistics regarding amino acid composition and pairing at different relative positions in the beta-strands. Analysis of the database reveals a 15.8% prevalence of significant ICBS interactions, the majority of which involve the formation of antiparallel beta-sheets and many of which involve the formation of dimers and oligomers. The frequencies of amino acids in ICBS interfaces are similar to those in intrachain beta-sheet interfaces. A full range of non-covalent interactions between side chains complement the hydrogen-bonding interactions between the main chains. Polar amino acids pair preferentially with polar amino acids and non-polar amino acids pair preferentially with non-polar amino acids among antiparallel (i, j) pairs. We anticipate that the statistics and insights gained from the database will guide the development of agents that control interchain beta-sheet interactions and that the database will help identify new protein interactions and targets for these agents. AVAILABILITY: The database is available at: http://www.igb.uci.edu/servers/icbs/

MOTIVATION: Over sufficiently long windows, complementary strands of DNA tend to have the same base composition. A few reports have indicated that this first-order parity rule extends at higher orders to oligonucleotide composition, at least in some organisms or taxa. However, the scientific literature falls short of providing a comprehensive study of reverse-complement symmetry at multiple orders and across the kingdom of life. It also lacks a characterization of this symmetry and a convincing explanation or clarification of its origin. RESULTS: We develop methods to measure and characterize symmetry at multiple orders, and analyze a wide set of genomes, encompassing single- and double-stranded RNA and DNA viruses, bacteria, archae, mitochondria, and eukaryota. We quantify symmetry at orders 1 to 9 for contiguous sequences and pools of coding and non-coding upstream regions, compare the observed symmetry levels to those predicted by simple statistical models, and factor out the effect of lower-order distributions. We establish the universality and variability range of first-order strand symmetry, as well as of its higher-order extensions, and demonstrate the existence of genuine high-order symmetric constraints. We show that ubiquitous reverse-complement symmetry does not result from a single cause, such as point mutation or recombination, but rather emerges from the combined effects of a wide spectrum of mechanisms operating at multiple orders and length scales.

MOTIVATION: The primary function of DNA is to carry genetic information through the genetic code. DNA, however, contains a variety of other signals related, for instance, to reading frame, codon bias, pairwise codon bias, splice sites and transcription regulation, nucleosome positioning and DNA structure. Here we study the relationship between the genetic code and DNA structure and address two questions. First, to which degree does the degeneracy of the genetic code and the acceptable amino acid substitution patterns allow for the superimposition of DNA structural signals to protein coding sequences? Second, is the origin or evolution of the genetic code likely to have been constrained by DNA structure? RESULTS: We develop an index for code flexibility with respect to DNA structure. Using five different di- or tri-nucleotide models of sequence-dependent DNA structure, we show that the standard genetic code provides a fair level of flexibility at the level of broad amino acid categories. Thus the code generally allows for the superimposition of any structural signal on any protein-coding sequence, through amino acid substitution. The flexibility observed at the level of single amino acids allows only for the superimposition of punctual and loosely positioned signals to conserved amino acid sequences. The degree of flexibility of the genetic code is low or average with respect to several classes of alternative codes. This result is consistent with the view that DNA structure is not likely to have played a significant role in the origin and evolution of the genetic code.

MOTIVATION: DNA structure plays an important role in a variety of biological processes. Different di- and tri-nucleotide scales have been proposed to capture various aspects of DNA structure including base stacking energy, propeller twist angle, protein deformability, bendability, and position preference. Yet, a general framework for the computational analysis and prediction of DNA structure is still lacking. Such a framework should in particular address the following issues: (1) construction of sequences with extremal properties; (2) quantitative evaluation of sequences with respect to a given genomic background; (3) automatic extraction of extremal sequences and profiles from genomic databases; (4) distribution and asymptotic behavior as the length N of the sequences increases; and (5) complete analysis of correlations between scales. RESULTS: We develop a general framework for sequence analysis based on additive scales, structural or other, that addresses all these issues. We show how to construct extremal sequences and calibrate scores for automatic genomic and database extraction. We show that distributions rapidly converge to normality as Nincreases. Pairwise correlations between scales depend both on background distribution and sequence length and rapidly converge to an analytically predictable asymptotic value. For di- and tri-nucleotide scales, normal behavior and asymptotic correlation values are attained over a characteristic window length of about 10-15 bp. With a uniform background distribution, pairwise correlations between empirically-derived scales remain relatively small and roughly constant at all lengths, except for propeller twist and protein deformability which are positively correlated. There is a positive (resp. negative) correlation between dinucleotide base stacking (resp. propeller twist and protein deformability) and AT-content that increases in magnitude with length. The framework is applied to the analysis of various DNA tandem repeats. We derive exact expressions for counting the number of repeat unit classes at all lengths. Tandem repeats are likely to result from a variety of different mechanisms, a fraction of which is likely to depend on profiles characterized by extreme structural features.