Generalizing the isothermal efficiency by using Gaussian distributions.

Unlike the Carnot heat engine efficiency published in 1824, an isothermal efficiency derived from thermodynamics and information theory can be applied to biological systems. The original approach by Pierce and Cutler in 1959 to derive the isothermal efficiency equation came from Shannon's channel capacity of 1949 and from Felker's 1952 determination of the minimum energy dissipation needed to gain a bit. In 1991 and 2010 Schneider showed how the isothermal efficiency equation can be applied to molecular machines and that this can be used to explain why several molecular machines are 70% efficient.

Restriction enzymes use a 24 dimensional coding space to recognize 6 base long DNA sequences.

Restriction enzymes recognize and bind to specific sequences on invading bacteriophage DNA. Like a key in a lock, these proteins require many contacts to specify the correct DNA sequence. Using information theory we develop an equation that defines the number of independent contacts, which is the dimensionality of the binding.

Elements in the λ immunity region regulate phage development: beyond the 'Genetic Switch'.

Genetic elements in the bacteriophage λ immunity region contribute to stable maintenance and synchronous induction of the integrated Escherichia coli prophage. There is a bistable switch between lysogenic and lytic growth that is orchestrated by the CI and Cro repressors acting on the lytic (P and P ) and lysogenic (P ) promoters, referred to as the Genetic Switch. Other less well-characterized elements in the phage immunity region include the P promoter and the immunity terminator, T .

Density of σ70 promoter-like sites in the intergenic regions dictates the redistribution of RNA polymerase during osmotic stress in Escherichia coli.

RNA polymerase (RNAP), the transcription machinery, shows dynamic binding across the genomic DNA under different growth conditions. The genomic features that selectively redistribute the limited RNAP molecules to dictate genome-wide transcription in response to environmental cues remain largely unknown. We chose the bacterial osmotic stress response model to determine genomic features that direct genome-wide redistribution of RNAP during the stress.

An Evolutionary/Biochemical Connection between Promoter- and Primer-Dependent Polymerases Revealed by Systematic Evolution of Ligands by Exponential Enrichment.

DNA polymerases (DNAPs) recognize 3' recessed termini on duplex DNA and carry out nucleotide catalysis. Unlike promoter-specific RNA polymerases (RNAPs), no sequence specificity is required for binding or initiation of catalysis. Despite this, previous results indicate that viral reverse transcriptases bind much more tightly to DNA primers that mimic the polypurine tract.

Genome-Wide Transcriptional Regulation and Chromosome Structural Arrangement by GalR in .

The regulatory protein, GalR, is known for controlling transcription of genes related to D-galactose metabolism in . Here, using a combination of experimental and bioinformatic approaches, we identify novel GalR binding sites upstream of several genes whose function is not directly related to D-galactose metabolism. Moreover, we do not observe regulation of these genes by GalR under standard growth conditions.

Identification of a Cryptic Bacterial Promoter in Mouse (mdr1a) P-Glycoprotein cDNA.

The efflux transporter P-glycoprotein (P-gp) is an important mediator of various pharmacokinetic parameters, being expressed at numerous physiological barriers and also in multidrug-resistant cancer cells. Molecular cloning of homologous cDNAs is an important tool for the characterization of functional differences in P-gp between species. However, plasmids containing mouse mdr1a cDNA display significant genetic instability during cloning in bacteria, indicating that mdr1a cDNA may be somehow toxic to bacteria, allowing only clones containing mutations that abrogate this toxicity to survive transformation.

Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts.

Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements.

An unusual feature associated with LEE1 P1 promoters in enteropathogenic Escherichia coli (EPEC).

Transcription start points in bacteria are influenced by the nature of the RNA polymerase·promoter interaction. For Escherichia coli RNA polymerase holoenzyme containing σ70, it is presumed that specific sequence in one or more of the -10, extended -10 and -35 elements of the promoter guides the RNAP to select the cognate start point. Here, we investigated the promoter driving expression of the LEE1 operon in enteropathogenic E.

A brief review of molecular information theory.

The idea that we could build molecular communications systems can be advanced by investigating how actual molecules from living organisms function. Information theory provides tools for such an investigation. This review describes how we can compute the average information in the DNA binding sites of any genetic control protein and how this can be extended to analyze its individual sites.

70% efficiency of bistate molecular machines explained by information theory, high dimensional geometry and evolutionary convergence.

The relationship between information and energy is key to understanding biological systems. We can display the information in DNA sequences specifically bound by proteins by using sequence logos, and we can measure the corresponding binding energy. These can be compared by noting that one of the forms of the second law of thermodynamics defines the minimum energy dissipation required to gain one bit of information.

Small membrane proteins found by comparative genomics and ribosome binding site models.

The correct annotation of genes encoding the smallest proteins is one of the biggest challenges of genome annotation, and perhaps more importantly, few annotated short open reading frames have been confirmed to correspond to synthesized proteins. We used sequence conservation and ribosome binding site models to predict genes encoding small proteins, defined as having 16-50 amino acids, in the intergenic regions of the Escherichia coli genome. We tested expression of these predicted as well as previously annotated genes by integrating the sequential peptide affinity tag directly upstream of the stop codon on the chromosome and assaying for synthesis using immunoblot assays.

Discovery of novel tumor suppressor p53 response elements using information theory.

An accurate method for locating genes under tumor suppressor p53 control that is based on a well-established mathematical theory and built using naturally occurring, experimentally proven p53 sites is essential in understanding the complete p53 network. We used a molecular information theory approach to create a flexible model for p53 binding. By searching around transcription start sites in human chromosomes 1 and 2, we predicted 16 novel p53 binding sites and experimentally demonstrated that 15 of the 16 (94%) sites were bound by p53.

Xeroderma pigmentosum-variant patients from America, Europe, and Asia.

Xeroderma pigmentosum-variant (XP-V) patients have sun sensitivity and increased skin cancer risk. Their cells have normal nucleotide excision repair, but have defects in the POLH gene encoding an error-prone polymerase, DNA polymerase eta (pol eta). To survey the molecular basis of XP-V worldwide, we measured pol eta protein in skin fibroblasts from putative XP-V patients (aged 8-66 years) from 10 families in North America, Turkey, Israel, Germany, and Korea.

Twenty Years of Delila and Molecular Information Theory: The Altenberg-Austin Workshop in Theoretical Biology Biological Information, Beyond Metaphor: Causality, Explanation, and Unification Altenberg, Austria, 11-14 July 2002.

A brief personal history is given about how information theory can be applied to binding sites of genetic control molecules on nucleic acids. The primary example used is ribosome binding sites in Escherichia coli. Once the sites are aligned, the information needed to describe the sites can be computed using Claude Shannon's method.

Discovery of Fur binding site clusters in Escherichia coli by information theory models.

Fur is a DNA binding protein that represses bacterial iron uptake systems. Eleven footprinted Escherichia coli Fur binding sites were used to create an initial information theory model of Fur binding, which was then refined by adding 13 experimentally confirmed sites. When the refined model was scanned across all available footprinted sequences, sequence walkers, which are visual depictions of predicted binding sites, frequently appeared in clusters that fit the footprints ( approximately 83% coverage).

Correlation between binding rate constants and individual information of E. coli Fis binding sites.

Individual protein binding sites on DNA can be measured in bits of information. This information is related to the free energy of binding by the second law of thermodynamics, but binding kinetics appear to be inaccessible from sequence information since the relative contributions of the on- and off-rates to the binding constant, and hence the free energy, are unknown. However, the on-rate could be independent of the sequence since a protein is likely to bind once it is near a site.

Anatomy of Escherichia coli sigma70 promoters.

Information theory was used to build a promoter model that accounts for the -10, the -35 and the uncertainty of the gap between them on a common scale. Helical face assignment indicated that base -7, rather than -11, of the -10 may be flipping to initiate transcription. We found that the sequence conservation of sigma70 binding sites is 6.

CorreLogo: an online server for 3D sequence logos of RNA and DNA alignments.

We present an online server that generates a 3D representation of properties of user-submitted RNA or DNA alignments. The visualized properties are information of single alignment columns, mutual information of two alignment positions as well as the position-specific fraction of gaps. The nucleotide composition of both single columns and column pairs is visualized with the help of color-coded 3D bars labeled with letters.

Comparative analysis of tandem T7-like promoter containing regions in enterobacterial genomes reveals a novel group of genetic islands.

Based on molecular information theory, 10 T7-like promoter models were built for the T7 group of phages and used to scan their host genomes and closely related genomes. 38 genomes were scanned and 12 clusters of tandem promoters were identified in nine enteropathogens. Comparative analysis of these tandem promoter-bearing regions reveals that they are similar to each other, forming prophage-like islands of 4-13 kb.

Information theory based T7-like promoter models: classification of bacteriophages and differential evolution of promoters and their polymerases.

Molecular information theory was used to create sequence logos and promoter models for eight phages of the T7 group: T7, phiA1122, T3, phiYeO3-12, SP6, K1-5, gh-1 and K11. When these models were used to scan the corresponding genomes, a significant gap in the individual information distribution was observed between functional promoter sites and other sequences, suggesting that the models can be used to identify new T7-like promoters. When a combined 76-site model was used to scan the eight phages, 108 of the total 109 promoters were found, while none were found for other T7-like phages, phiKMV, P60, VpV262, SIO1, PaP3, Xp10, P-SSP7 and Ppu40, indicating that these phages do not belong to the T7 group.

Consensus sequence Zen.

Consensus sequences are widely used in molecular biology but they have many flaws. As a result, binding sites of proteins and other molecules are missed during studies of genetic sequences and important biological effects cannot be seen. Information theory provides a mathematically robust way to avoid consensus sequences.

Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene: mutations result in reduced XPC mRNA levels that correlate with cancer risk.

The lariat branch point sequence (BPS) is crucial for splicing of human nuclear pre-mRNA yet BPS mutations have infrequently been reported to cause human disease. Using an inverse RT-PCR technique we mapped two BPS to the adenosine residues at positions -4 and -24 in intron 3 of the human XPC DNA repair gene. We identified homozygous mutations in each of these BPS in two newly diagnosed Turkish families with the autosomal recessive disorder xeroderma pigmentosum (XP).

Molecular flip-flops formed by overlapping Fis sites.

The DNA-binding protein Fis frequently uses pairs of sites 7 or 11 base pairs (bp) apart. Two overlapping Fis sites separated by 11 bp are found in the Escherichia coli origin of chromosomal replication. Only one of these sites is bound by Fis at a time, so the structure is a molecular flip-flop that could direct alternative firing of replication complexes in opposite directions.