Dataset Information

Observation of the Unbiased Conformers of Putative DNA-Scaffold Ribosugars.

ABSTRACT: The constitution, configuration, and flexibility of the core sugars of DNA molecules alter their function in diverse roles. Conformational itineraries of the ribofuranosides (fs) have long been known to finely determine rates of processing, yet we also know that, strikingly, semifunctional DNAs containing pyranosides (ps) or other configurations can be created, suggesting sufficient but incompletely understood plasticity. The multiple conformers involved in such processes are necessarily influenced by context and environment: solvent, hosts, ligands. Notably, however, to date the unbiased, "naked" conformers have not been experimentally determined. Here, the inherent conformational biases of DNA scaffold deoxyribosides in unsolvated and solvated forms have now been defined using gas-phase microwave and solution-phase NMR spectroscopies coupled with computational analyses and exploitation of critical differences between natural-abundance isotopologues. Serial determination of precise, individual spectra for conformers of these 25 isotopologues in alpha (?-d) and beta (?-d); pyrano (p) and furano (f) methyl 2-deoxy-d-ribosides gave not only unprecedented atomic-level resolution structures of associated conformers but also their quantitative populations. Together these experiments revealed that typical ²E and ³E conformations of the sugar found in complex DNA structures are not inherently populated. Moreover, while both OH-5' and OH-3' are constrained by intramolecular hydrogen bonding in the unnatural ?f scaffold, OH-3' is "born free" in the "naked" lowest lying energy conformer of natural ?f. Consequently, upon solvation, unnatural ?f is strikingly less perturbable (retaining ²T₁ conformation in vacuo and water) than natural ?f. Unnatural ?p and ?p ribosides also display low conformational perturbability. These first experimental data on inherent, unbiased conformers therefore suggest that it is the background of conformational flexibility of ?f that may have led to its emergence out of multiple possibilities as the sugar scaffold for "life's code" and suggest a mechanism by which the resulting freedom of OH-3' (and hence accessibility as a nucleophile) in ?f may drive preferential processing and complex structure formation, such as replicative propagation of DNA from 5'-to-3'.

SUBMITTER: Calabrese C

PROVIDER: S-EPMC7047431 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Observation of the Unbiased Conformers of Putative DNA-Scaffold Ribosugars.

Calabrese Camilla C Uriarte Iciar I Insausti Aran A Vallejo-López Montserrat M Basterretxea Francisco J FJ Cochrane Stephen A SA Davis Benjamin G BG Corzana Francisco F Cocinero Emilio J EJ

ACS central science 20200218 2

The constitution, configuration, and flexibility of the core sugars of DNA molecules alter their function in diverse roles. Conformational itineraries of the ribofuranosides (<i>f</i>s) have long been known to finely determine rates of processing, yet we also know that, strikingly, semifunctional DNAs containing pyranosides (<i>p</i>s) or other configurations can be created, suggesting sufficient but incompletely understood plasticity. The multiple conformers involved in such processes are neces ...[more]

PMID: 32123748

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Project description:BackgroundPubChem is a free and open public resource for the biological activities of small molecules. With many tens of millions of both chemical structures and biological test results, PubChem is a sizeable system with an uneven degree of available information. Some chemical structures in PubChem include a great deal of biological annotation, while others have little to none. To help users, PubChem pre-computes "neighboring" relationships to relate similar chemical structures, which may have similar biological function. In this work, we introduce a "Similar Conformers" neighboring relationship to identify compounds with similar 3-D shape and similar 3-D orientation of functional groups typically used to define pharmacophore features.ResultsThe first two diverse 3-D conformers of 26.1 million PubChem Compound records were compared to each other, using a shape Tanimoto (ST) of 0.8 or greater and a color Tanimoto (CT) of 0.5 or greater, yielding 8.16 billion conformer neighbor pairs and 6.62 billion compound neighbor pairs, with an average of 253 "Similar Conformers" compound neighbors per compound. Comparing the 3-D neighboring relationship to the corresponding 2-D neighboring relationship ("Similar Compounds") for molecules such as caffeine, aspirin, and morphine, one finds unique sets of related chemical structures, providing additional significant biological annotation. The PubChem 3-D neighboring relationship is also shown to be able to group a set of non-steroidal anti-inflammatory drugs (NSAIDs), despite limited PubChem 2-D similarity.In a study of 4,218 chemical structures of biomedical interest, consisting of many known drugs, using more diverse conformers per compound results in more 3-D compound neighbors per compound; however, the overlap of the compound neighbor lists per conformer also increasingly resemble each other, being 38% identical at three conformers and 68% at ten conformers. Perhaps surprising is that the average count of conformer neighbors per conformer increases rather slowly as a function of diverse conformers considered, with only a 70% increase for a ten times growth in conformers per compound (a 68-fold increase in the conformer pairs considered).Neighboring 3-D conformers on the scale performed, if implemented naively, is an intractable problem using a modest sized compute cluster. Methodology developed in this work relies on a series of filters to prevent performing 3-D superposition optimization, when it can be determined that two conformers cannot possibly be a neighbor. Most filters are based on Tanimoto equation volume constraints, avoiding incompatible conformers; however, others consider preliminary superposition between conformers using reference shapes.ConclusionThe "Similar Conformers" 3-D neighboring relationship locates similar small molecules of biological interest that may go unnoticed when using traditional 2-D chemical structure graph-based methods, making it complementary to such methodologies. The computational cost of 3-D similarity methodology on a wide scale, such as PubChem contents, is a considerable issue to overcome. Using a series of efficient filters, an effective throughput rate of more than 150,000 conformers per second per processor core was achieved, more than two orders of magnitude faster than without filtering.

Dataset Information

Observation of the Unbiased Conformers of Putative DNA-Scaffold Ribosugars.

Publications

Observation of the Unbiased Conformers of Putative DNA-Scaffold Ribosugars.

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