Similarity Analysis of Computer-Generated and Commercial Libraries for Targeted Biocompatible Coded Amino Acid Replacement.

Many non-natural amino acids can be incorporated by biological systems into coded functional peptides and proteins. For such incorporations to be effective, they must not only be compatible with the desired function but also evade various biochemical error-checking mechanisms. The underlying molecular mechanisms are complex, and this problem has been approached previously largely by expert perception of isomer compatibility, followed by empirical study.

Comparative Evaluation of Electron Ionization Mass Spectral Prediction Methods.

During the past decade promising methods for computational prediction of electron ionization mass spectra have been developed. The most prominent ones are based on quantum chemistry (QCEIMS) and machine learning (CFM-EI, NEIMS). Here we provide a threefold comparison of these methods with respect to spectral prediction and compound identification.

Alternating co-synthesis of glycol nucleic acid (GNA) monomers with dicarboxylic acids drying.

We report the co-polymerization of glycol nucleic acid (GNA) monomers with unsubstituted and substituted dicarboxylic acid linkers under plausible early Earth aqueous dry-down conditions. Both linear and branched co-polymers are produced. Mechanistic aspects of the reaction and potential roles of these polymers in prebiotic chemistry are discussed.

A Closer Look at Non-random Patterns Within Chemistry Space for a Smaller, Earlier Amino Acid Alphabet.

Recent findings, in vitro and in silico, are strengthening the idea of a simpler, earlier stage of genetically encoded proteins which used amino acids produced by prebiotic chemistry. These findings motivate a re-examination of prior work which has identified unusual properties of the set of twenty amino acids found within the full genetic code, while leaving it unclear whether similar patterns also characterize the subset of prebiotically plausible amino acids. We have suggested previously that this ambiguity may result from the low number of amino acids recognized by the definition of prebiotic plausibility used for the analysis.

An open source computational workflow for the discovery of autocatalytic networks in abiotic reactions.

A central question in origins of life research is how non-entailed chemical processes, which simply dissipate chemical energy because they can do so due to immediate reaction kinetics and thermodynamics, enabled the origin of highly-entailed ones, in which concatenated kinetically and thermodynamically favorable processes enhanced some processes over others. Some degree of molecular complexity likely had to be supplied by environmental processes to produce entailed self-replicating processes. The origin of entailment, therefore, must connect to fundamental chemistry that builds molecular complexity.

Open questions in understanding life's origins.

The chemical space of prebiotic chemistry is extremely large, while extant biochemistry uses only a few thousand interconnected molecules. Here we discuss how the connection between these two regimes can be investigated, and explore major outstanding questions in the origin of life.

One Among Millions: The Chemical Space of Nucleic Acid-Like Molecules.

Biology encodes hereditary information in DNA and RNA, which are finely tuned to their biological functions and modes of biological production. The central role of nucleic acids in biological information flow makes them key targets of pharmaceutical research. Indeed, other nucleic acid-like polymers can play similar roles to natural nucleic acids both and ; yet despite remarkable advances over the last few decades, much remains unknown regarding which structures are compatible with molecular information storage.

Adaptive Properties of the Genetically Encoded Amino Acid Alphabet Are Inherited from Its Subsets.

Life uses a common set of 20 coded amino acids (CAAs) to construct proteins. This set was likely canonicalized during early evolution; before this, smaller amino acid sets were gradually expanded as new synthetic, proofreading and coding mechanisms became biologically available. Many possible subsets of the modern CAAs or other presently uncoded amino acids could have comprised the earlier sets.

Systems chemical analytics: introduction to the challenges of chemical complexity analysis.

Understanding complex (bio/geo)systems is a pivotal challenge in modern sciences that fuels a constant development of modern analytical technology, finding innovative solutions to resolve and analyse. In this introductory paper to the Faraday Discussion "Challenges in the analysis of complex natural systems", we aim to present concepts of complexity, and complex chemistry in systems subjected to biotic and abiotic transformations, and introduce the analytical possibilities to disentangle chemical complexity into its elementary parts (i.e.

RSPO3 is a prognostic biomarker and mediator of invasiveness in prostate cancer.

Background: While prostate cancer can often manifest as an indolent disease, the development of locally-advanced or metastatic disease can cause significant morbidity or mortality. Elucidation of molecular mechanisms contributing to disease progression is crucial for more accurate prognostication and effective treatments. R-Spondin 3 (RSPO3) is a protein previously implicated in the progression of colorectal and lung cancers.

Computational exploration of the chemical structure space of possible reverse tricarboxylic acid cycle constituents.

The reverse tricarboxylic acid (rTCA) cycle has been explored from various standpoints as an idealized primordial metabolic cycle. Its simplicity and apparent ubiquity in diverse organisms across the tree of life have been used to argue for its antiquity and its optimality. In 2000 it was proposed that chemoinformatics approaches support some of these views.

Exploring astrobiology using molecular structure generation.

The origin of life is typically understood as a transition from inanimate or disorganized matter to self-organized, 'animate' matter. This transition probably took place largely in the context of organic compounds, and most approaches, to date, have focused on using the organic chemical composition of modern organisms as the main guide for understanding this process. However, it has gradually come to be appreciated that biochemistry, as we know it, occupies a minute volume of the possible organic 'chemical space'.

Lipid signalling mediated by PLD/PA modulates proline and HO levels in barley seedlings exposed to short- and long-term chilling stress.

Phospholipase D (PLD) hydrolyses phospholipids to yield phosphatidic acid (PA) and a head group, and is involved in responses to a variety of environmental stresses, including chilling and freezing stress. Barley responses to chilling stress (induced by incubating seedlings at 4 °C) are dynamic and the duration of stress, either short (0-180 min) or long-term (24-36 h) had a significant impact on the response. We investigated the roles of PLD/PA in responses of barley (Hordeum vulgare) seedlings to short and long-term chilling stress, based on regulation of proline and reactive oxygen species (ROS) levels.

227 Views of RNA: Is RNA Unique in Its Chemical Isomer Space?

Ribonucleic acid (RNA) is one of the two nucleic acids used by extant biochemistry and plays a central role as the intermediary carrier of genetic information in transcription and translation. If RNA was involved in the origin of life, it should have a facile prebiotic synthesis. A wide variety of such syntheses have been explored.

Extraordinarily adaptive properties of the genetically encoded amino acids.

Using novel advances in computational chemistry, we demonstrate that the set of 20 genetically encoded amino acids, used nearly universally to construct all coded terrestrial proteins, has been highly influenced by natural selection. We defined an adaptive set of amino acids as one whose members thoroughly cover relevant physico-chemical properties, or "chemistry space." Using this metric, we compared the encoded amino acid alphabet to random sets of amino acids.

Beyond terrestrial biology: charting the chemical universe of α-amino acid structures.

α-Amino acids are fundamental to biochemistry as the monomeric building blocks with which cells construct proteins according to genetic instructions. However, the 20 amino acids of the standard genetic code represent a tiny fraction of the number of α-amino acid chemical structures that could plausibly play such a role, both from the perspective of natural processes by which life emerged and evolved, and from the perspective of human-engineered genetically coded proteins. Until now, efforts to describe the structures comprising this broader set, or even estimate their number, have been hampered by the complex combinatorial properties of organic molecules.

Small Molecule Identification with MOLGEN and Mass Spectrometry.

This paper details the MOLGEN entries for the 2012 CASMI contest for small molecule identification to demonstrate structure elucidation using structure generation approaches. Different MOLGEN programs were used for different categories, including MOLGEN-MS/MS for Category 1, MOLGEN 3.5 and 5.

Comparative phytohormone profiles, lipid kinase and lipid phosphatase activities in barley aleurone, coleoptile, and root tissues.

We analyzed lipid kinase and lipid phosphatase activities and determined endogenous phytohormone levels by liquid chromatography-tandem mass spectrometry in root and coleoptile tissues following germination of barley (Hordeum vulgare) seeds. The enzymes showing highest activity in aleurone cells were diacylglycerol kinase (DAG-k, EC 2.7.

Consensus structure elucidation combining GC/EI-MS, structure generation, and calculated properties.

This article explores consensus structure elucidation on the basis of GC/EI-MS, structure generation, and calculated properties for unknown compounds. Candidate structures were generated using the molecular formula and substructure information obtained from GC/EI-MS spectra. Calculated properties were then used to score candidates according to a consensus approach, rather than filtering or exclusion.

Automated strategies to identify compounds on the basis of GC/EI-MS and calculated properties.

The identification of unknown compounds based on GC/EI-MS spectrum and structure generation techniques has been improved by combining a number of strategies into a programmed sequence. The program MOLGEN-MS is used to determine the molecular formula and incorporate substructural information to generate all structures matching the mass spectral information. Mass spectral fragments are then predicted for each structure and compared with the experimental spectrum using a match value.

Matching structures to mass spectra using fragmentation patterns: are the results as good as they look?

Three programs were assessed for their ability to predict mass spectral fragmentation patterns for all constitutional isomers of an experimental low-resolution electron impact mass spectrum (EI-MS), given the molecular formula, and use this information to identify the "correct structure". MOLGEN 3.5 was used to generate the structures, while all spectra were extracted from the NIST database.

The use of MS classifiers and structure generation to assist in the identification of unknowns in effect-directed analysis.

Structure generation and mass spectral classifiers have been incorporated into a new method to gain further information from low-resolution GC-MS spectra and subsequently assist in the identification of toxic compounds isolated using effect-directed fractionation. The method has been developed for the case where little analytical information other than the mass spectrum is available, common, for example, in effect-directed analysis (EDA), where further interpretation of the mass spectra is necessary to gain additional information about unknown peaks in the chromatogram. Structure generation from a molecular formula alone rapidly leads to enormous numbers of structures; hence reduction of these numbers is necessary to focus identification or confirmation efforts.

High-precision frequency measurements: indispensable tools at the core of the molecular-level analysis of complex systems.

This perspective article provides an assessment of the state-of-the-art in the molecular-resolution analysis of complex organic materials. These materials can be divided into biomolecules in complex mixtures (which are amenable to successful separation into unambiguously defined molecular fractions) and complex nonrepetitive materials (which cannot be purified in the conventional sense because they are even more intricate). Molecular-level analyses of these complex systems critically depend on the integrated use of high-performance separation, high-resolution organic structural spectroscopy and mathematical data treatment.

y-Randomization and its variants in QSPR/QSAR.

y-Randomization is a tool used in validation of QSPR/QSAR models, whereby the performance of the original model in data description (r2) is compared to that of models built for permuted (randomly shuffled) response, based on the original descriptor pool and the original model building procedure. We compared y-randomization and several variants thereof, using original response, permuted response, or random number pseudoresponse and original descriptors or random number pseudodescriptors, in the typical setting of multilinear regression (MLR) with descriptor selection. For each combination of number of observations (compounds), number of descriptors in the final model, and number of descriptors in the pool to select from, computer experiments using the same descriptor selection method result in two different mean highest random r2 values.

Molecules in silico: a graph description of chemical reactions.

A general mathematical description, mostly in terms of graph theory, is given for reactions of organic chemistry. The corresponding computer program generates all products that can result from a given set of starting materials interacting according to a given set of reaction schemes. Example reactions from combinatorial chemistry, synthetic organic chemistry, and mass spectroscopic structure elucidation are considered in detail.