Direct interplay between stereochemistry and conformational preferences in aminoacylated oligoribonucleotides
To address the structural and dynamical consequences of amino-acid attachment at 2′- or 3′-hydroxyls of the terminal ribose in oligoribonucleotides, we have performed an extensive set of molecular dynamics simulations of model aminoacylated RNA trinucleotides. Our simulations suggest that 3′-modified trinucleotides exhibit higher solvent exposure of the aminoacylester bond and may be more susceptible to hydrolysis than their 2′ counterparts. Moreover, we observe an invariant adoption of well-defined collapsed and extended conformations for both stereoisomers. We show that the average conformational preferences of aminoacylated trinucleotides are determined by their nucleotide composition and are fine-tuned by amino-acid attachment. Conversely, solvent exposure of the aminoacylester bond depends on the attachment site, the nature of attached amino acid and the strength of its interactions with the bases. Importantly, aminoacylated CCA trinucleotides display a systematically higher solvent exposure of the aminoacylester bond and a weaker dependence of such exposure on sidechain interactions than other trinucleotides. These features could facilitate hydrolytic release of the amino acid, especially for 3′ attachment, and may have contributed to CCA becoming the universal acceptor triplet in tRNAs. Our results provide novel atomistic details about fundamental aspects of biological translation and furnish clues about its primordial origins.
The recently developed NMR techniques enable estimation of protein configurational entropy change from the change in the average methyl order parameters. This experimental observable, however, does not directly measure the contribution of intramolecular couplings, protein main-chain motions, or angular dynamics. Here, we carry out a self-consistent computational analysis of the impact of these missing contributions on an extensive set of molecular dynamics simulations of different proteins undergoing binding. Specifically, we compare the configurational entropy change in protein complex formation as obtained by the maximum information spanning tree approximation (MIST), which treats the above entropy contributions directly, and the change in the average NMR methyl and NH order parameters. Our parallel implementation of MIST allows us to treat hard angular degrees of freedom as well as couplings up to full pairwise order explicitly, while still involving a high degree of sampling and tackling molecules of biologically relevant sizes. First, we demonstrate a remarkably strong linear relationship between the total configurational entropy change and the average change in both methyl and backbone-NH order parameters. Second, in contrast to canonical assumptions, we show that the main-chain and angular terms contribute significantly to the overall configurational entropy change and also scale linearly with it. Consequently, linear models starting from the average methyl order parameters are able to capture the contribution of main-chain and angular terms well. After applying the quantum-mechanical harmonic oscillator entropy formalism, we establish a similarly strong linear relationship for X-ray crystallographic B-factors. Finally, we demonstrate that the observed linear relationships remain robust against drastic undersampling and argue that they reflect an intrinsic property of compact proteins. Despite their remarkable strength, however, the above linear relationships yield estimates of configurational entropy change whose accuracy appears to be sufficient for qualitative applications only.
In this paper, we study the Maximum Happy Vertices and the Maximum Happy Edges problems (MHV and MHE for short). Very recently, the problems attracted a lot of attention and were studied in Agrawal ’17, Aravind et al. ’16, Choudhari and Reddy ’18, Misra and Reddy ’17. Main focus of our work is lower bounds on the computational complexity of these problems. Established lower bounds can be divided into the following groups: NP-hardness of the above guarantee parameterization, kernelization lower bounds (answering questions of Misra and Reddy ’17), exponential lower bounds under the Set Cover Conjecture and the Exponential Time Hypothesis, and inapproximability results. Moreover, we present an O∗(ℓk)O∗(ℓk) randomized algorithm for MHV and an O∗(2k)O∗(2k) algorithm for MHE, where ℓℓ is the number of colors used and k is the number of required happy vertices or edges. These algorithms cannot be improved to subexponential taking proved lower bounds into account.
The current state of information systems of the Pushchino Research Center of the Russian Academy of Sciences to successfully solve the problems of computational biology.
Optimization Approaches for Solving String Selection Problems provides an overview of optimization methods for a wide class of genomics-related problems in relation to the string selection problems. This class of problems addresses the recognition of similar characteristics or differences within biological sequences. Specifically, this book considers a large class of problems, ranging from the closest string and substring problems, to the farthest string and substring problems, to the far from most string problem. Each problem includes a detailed description, highlighting both biological and mathematical features and presents state-of-the-art approaches.
Poly(ADP-ribose) glycohydrolase (PARG) regulates cellular poly(ADP-ribose) (PAR) levels by rapidly cleaving glycosidic bonds between ADP-ribose units. PARG interacts with proliferating cell nuclear antigen (PCNA) and is strongly recruited to DNA damage sites in a PAR- and PCNA-dependent fashion. Here we identified PARG acetylation site K409 that is essential for its interaction with PCNA, its localization within replication foci and its recruitment to DNA damage sites. We found K409 to be part of a non-canonical PIP-box within the PARG disordered regulatory region. The previously identified putative N-terminal PIP-box does not bind PCNA directly but contributes to PARG localization within replication foci. X-ray structure and MD simulations reveal that the PARG non-canonical PIP-box binds PCNA in a manner similar to other canonical PIP-boxes and may represent a new type of PIP-box. While the binding of previously described PIP-boxes is based on hydrophobic interactions, PARG PIP-box binds PCNA via both stabilizing hydrophobic and fine-tuning electrostatic interactions. Our data explain the mechanism of PARG-PCNA interaction through a new PARG PIP-box that exhibits non-canonical sequence properties but a canonical mode of PCNA binding.
In order to fully understand the microscopic origins of binding specificity between nucleic acids and proteins, it is imperative to study the dependence of the binding preferences between nucleobases and protein side chains on the properties of the environment. Here, we employ molecular dynamics simulations and umbrella sampling to derive the potentials of mean force and the associated absolute binding free energies between the four standard RNA nucleobases and the side chains of aspartic acid and tryptophan in water/methanol mixtures exhibiting a wide range of dielectric constants. In addition to their opposing character when it comes to hydrophobicity, aspartate and tryptophan side chains were chosen because they exhibit the greatest change in binding free energies with nucleobases between pure water and methanol environments. We exploit a strong linear dependence of the derived ΔG values on the mole fraction of methanol to estimate the binding free energies of all possible combinations of different standard RNA nucleobases and side chains at multiple values of dielectric constants. Finally, we critically assess the recently proposed complementarity hypothesis concerning direct, coaligned binding between mRNAs and their cognate proteins in light of the present results.
One of the key advances in genome assembly that has led to a significant improvement in contig lengths has been improved algorithms for utilization of paired reads (mate-pairs). While in most assemblers, mate-pair information is used in a post-processing step, the recently proposed Paired de Bruijn Graph (PDBG) approach incorporates the mate-pair information directly in the assembly graph structure. However, the PDBG approach faces difficulties when the variation in the insert sizes is high. To address this problem, we first transform mate-pairs into edge-pair histograms that allow one to better estimate the distance between edges in the assembly graph that represent regions linked by multiple mate-pairs. Further, we combine the ideas of mate-pair transformation and PDBGs to construct new data structures for genome assembly: pathsets and pathset graphs.
Papers about natural protection territories
Many environmental stimuli present a quasi-rhythmic structure at different timescales that the brain needs to decompose and integrate. Cortical oscillations have been proposed as instruments of sensory de-multiplexing, i.e., the parallel processing of different frequency streams in sensory signals. Yet their causal role in such a process has never been demonstrated. Here, we used a neural microcircuit model to address whether coupled theta–gamma oscillations, as observed in human auditory cortex, could underpin the multiscale sensory analysis of speech. We show that, in continuous speech, theta oscillations can flexibly track the syllabic rhythm and temporally organize the phoneme-level response of gamma neurons into a code that enables syllable identification. The tracking of slow speech fluctuations by theta oscillations, and its coupling to gamma-spiking activity both appeared as critical features for accurate speech encoding. These results demonstrate that cortical oscillations can be a key instrument of speech de-multiplexing, parsing, and encoding.
Hypoxia of trophoblast cells is an important regulator of normal development of the placenta. However, some pathological states associated with hypoxia, e.g. preeclampsia, impair the functions of placental cells. Oxyquinoline derivative inhibits HIF-prolyl hydroxylase by stabilizing HIF-1 transcription complex, thus modeling cell response to hypoxia. In human choriocarcinoma cells BeWo b30 (trophoblast model), oxyquinoline increased the expression of a core hypoxia response genes along with up-regulation of NOS3, PDK1, and BNIP3 genes and down-regulation of the PPARGC1B gene. These changes in the expression profile attest to activation of the metabolic cell reprogramming mechanisms aimed at reducing oxygen consumption by enabling the switch from aerobic to anaerobic glucose metabolism and the respective decrease in number of mitochondria. The possibility of practical use of the therapeutic properties of oxyquinoline derivatives is discussed.