Dinucleotide controlled null models for comparative RNA gene prediction

<p>Abstract</p> <p>Background</p> <p>Comparative prediction of RNA structures can be used to identify functional noncoding RNAs in genomic screens. It was shown recently by Babak <it>et al</it>. [BMC Bioinformatics. 8:33] that RNA gene prediction programs can be biased by the genomic dinucleotide content, in particular those programs using a thermodynamic folding model including stacking energies. As a consequence, there is need for dinucleotide-preserving control strategies to assess the significance of such predictions. While there have been randomization algorithms for single sequences for many years, the problem has remained challenging for multiple alignments and there is currently no algorithm available.</p> <p>Results</p> <p>We present a program called SISSIz that simulates multiple alignments of a given average dinucleotide content. Meeting additional requirements of an accurate null model, the randomized alignments are on average of the same sequence diversity and preserve local conservation and gap patterns. We make use of a phylogenetic substitution model that includes overlapping dependencies and site-specific rates. Using fast heuristics and a distance based approach, a tree is estimated under this model which is used to guide the simulations. The new algorithm is tested on vertebrate genomic alignments and the effect on RNA structure predictions is studied. In addition, we directly combined the new null model with the RNAalifold consensus folding algorithm giving a new variant of a thermodynamic structure based RNA gene finding program that is not biased by the dinucleotide content.</p> <p>Conclusion</p> <p>SISSIz implements an efficient algorithm to randomize multiple alignments preserving dinucleotide content. It can be used to get more accurate estimates of false positive rates of existing programs, to produce negative controls for the training of machine learning based programs, or as standalone RNA gene finding program. Other applications in comparative genomics that require randomization of multiple alignments can be considered.</p> <p>Availability</p> <p>SISSIz is available as open source C code that can be compiled for every major platform and downloaded here: <url>http://sourceforge.net/projects/sissiz</url>.</p

Diastereoselective Radical Hydrogen Transfer Reactions using N‑Heterocyclic Carbene Boranes

Reported herein are the first diastereoselective and Lewis acid-mediated radical reactions of N-heterocyclic carbene (NHC) boranes. We applied these reactions to the synthesis of four propionate diastereoisomers combining an aldol reaction, followed by a stereoselective radical-based reduction in which the NHC borane serves as the hydrogen donor, thus obviating the use of tin-based reagents. The 2,3-<i>syn</i> isomer is obtained by combining an NHC-borane and a Lewis acid (MgBr₂·OEt₂), while using a reverse polarity strategy provides the 2,3-<i>anti</i> isomer

Study of the Endocyclic versus Exocyclic C–O Bond Cleavage Pathways of α- and β‑Methyl Furanosides

The activation and ring-opening of methyl furanosides in the four natural sugar scaffolds (ribo, lyxo, arabino, and xylo) efficiently afforded acyclic thioacetals with high S_N2-like selectivity at the acetal center in the presence of Me₂BBr and thiophenol. The stereochemical outcome of these reactions provides important mechanistic insights into the activation pathway of five-membered semicyclic acetals. The thioacetal products should find applications in oligosaccharides synthesis and allow further development of acyclic strategies for the synthesis of novel nucleoside analogues

Diastereoselective and regioselective synthesis of adenosine thionucleoside analogues using an acyclic approach

An acyclic approach to synthesize thiofuranoside N-glycosides bearing an adenine nucleobase is presented herein. This approach provides a significant improvement in terms of regio-and diastereoselectivity as compared to the current paradigms used for their formation. Activation of acyclic dithioacetal substrates bearing either a C2'-alkoxy or fluoro group and coupling with purine nucleobases selectively generates 1',2'-syn thioaminals. The regiochemistry of the nucleobase coupling (N7 or N9) can also be controlled by using either silylated or unsilylated purines. A subsequent SN2-like cyclization of these 1',2'-syn acyclic thioaminals results in the desired 1',2'-cis thionucleoside analogues.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Investigation of Diastereoselective Acyclic α‑Alkoxydithioacetal Substitutions Involving Thiacarbenium Intermediates

Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin–Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through S_N2-like transition structures (TS <b>A</b> and <b>D</b>), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C–N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔ<i>G</i>^⧧ (<i>G</i>^{TS<b>A</b>–TS<b>D</b>}) obtained <i>in silico</i> are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals

Identification of a C2′-fluorinated SAH analogue

The progress towards the development of a nucleoside analogue with inhibitory properties against SETDB1, a histone methyltransferase (HMT) is described. Based on the structure of the natural cofactor S-adenosyl-L-methionine (SAM), novel fluorinated nucleoside analogues were synthesized. Two of these compounds bearing a C2'-F and C5'-primary amine moiety showed moderate inhibition of SETDB1, a lysine HMT for which there is only one reported inhibitor.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author