Classification and Energetics of the Base-Phosphate Interactions in RNA

Structured RNA molecules form complex 3D architectures stabilized by multiple interactions involving the nucleotide base, sugar and phosphate moieties. A significant percentage of the bases in structured RNA molecules in the Protein Data Bank (PDB) hydrogen-bond with phosphates of other nucleotides. By extracting and superimposing base-phosphate (BPh) interactions from a reduced-redundancy subset of 3D structures from the PDB, we identified recurrent phosphate-binding sites on the RNA bases. Quantum chemical calculations were carried out on model systems representing each BPh interaction. The calculations show that the centers of each cluster obtained from the structure superpositions correspond to energy minima on the potential energy hypersurface. The calculations also show that the most stable phosphate-binding sites occur on the Watson-Crick edge of guanine and the Hoogsteen edge of cytosine. We modified the \u27Find RNA 3D\u27 (FR3D) software suite to automatically find and classify BPh interactions. Comparison of the 3D structures of the 16S and 23S rRNAs of Escherichia coli and Thermus thermophilus revealed that most BPh interactions are phylogenetically conserved and they occur primarily in hairpin, internal or junction loops or as part of tertiary interactions. Bases that form BPh interactions, which are conserved in the rRNA 3D structures are also conserved in homologous rRNA sequence alignments

Classification and energetics of the base-phosphate interactions in RNA

Structured RNA molecules form complex 3D architectures stabilized by multiple interactions involving the nucleotide base, sugar and phosphate moieties. A significant percentage of the bases in structured RNA molecules in the Protein Data Bank (PDB) hydrogen-bond with phosphates of other nucleotides. By extracting and superimposing base-phosphate (BPh) interactions from a reduced-redundancy subset of 3D structures from the PDB, we identified recurrent phosphate-binding sites on the RNA bases. Quantum chemical calculations were carried out on model systems representing each BPh interaction. The calculations show that the centers of each cluster obtained from the structure superpositions correspond to energy minima on the potential energy hypersurface. The calculations also show that the most stable phosphate-binding sites occur on the Watson–Crick edge of guanine and the Hoogsteen edge of cytosine. We modified the ‘Find RNA 3D' (FR3D) software suite to automatically find and classify BPh interactions. Comparison of the 3D structures of the 16S and 23S rRNAs of Escherichia coli and Thermus thermophilus revealed that most BPh interactions are phylogenetically conserved and they occur primarily in hairpin, internal or junction loops or as part of tertiary interactions. Bases that form BPh interactions, which are conserved in the rRNA 3D structures are also conserved in homologous rRNA sequence alignments

Classification and energetics of the base-phosphate interactions in RNA

Structured RNA molecules form complex 3D architectures stabilized by multiple interactions involving the nucleotide base, sugar and phosphate moieties. A significant percentage of the bases in structured RNA molecules in the Protein Data Bank (PDB) hydrogen-bond with phosphates of other nucleotides. By extracting and superimposing base-phosphate (BPh) interactions from a reduced-redundancy subset of 3D structures from the PDB, we identified recurrent phosphate-binding sites on the RNA bases. Quantum chemical calculations were carried out on model systems representing each BPh interaction. The calculations show that the centers of each cluster obtained from the structure superpositions correspond to energy minima on the potential energy hypersurface. The calculations also show that the most stable phosphate-binding sites occur on the Watson–Crick edge of guanine and the Hoogsteen edge of cytosine. We modified the ‘Find RNA 3D' (FR3D) software suite to automatically find and classify BPh interactions. Comparison of the 3D structures of the 16S and 23S rRNAs of Escherichia coli and Thermus thermophilus revealed that most BPh interactions are phylogenetically conserved and they occur primarily in hairpin, internal or junction loops or as part of tertiary interactions. Bases that form BPh interactions, which are conserved in the rRNA 3D structures are also conserved in homologous rRNA sequence alignments

Molecular dynamics simulations of RNA kissing–loop motifs reveal structural dynamics and formation of cation-binding pockets

Explicit solvent molecular dynamics (MD) simulations were carried out for three RNA kissing–loop complexes. The theoretical structure of two base pairs (2 bp) complex of H3 stem–loop of Moloney murine leukemia virus agrees with the NMR structure with modest violations of few NMR restraints comparable to violations present in the NMR structure. In contrast to the NMR structure, however, MD shows relaxed intermolecular G-C base pairs. The core region of the kissing complex forms a cation-binding pocket with highly negative electrostatic potential. The pocket shows nanosecond-scale breathing motions coupled with oscillations of the whole molecule. Additional simulations were carried out for 6 bp kissing complexes of the DIS HIV-1 subtypes A and B. The simulated structures agree well with the X-ray data. The subtype B forms a novel four-base stack of bulged-out adenines. Both 6 bp kissing complexes have extended cation-binding pockets in their central parts. While the pocket of subtype A interacts with two hexacoordinated Mg(2+) ions and one sodium ion, pocket of subtype B is filled with a string of three delocalized Na(+) ions with residency times of individual cations 1–2 ns. The 6 bp complexes show breathing motions of the cation-binding pockets and loop major grooves

Chemomimesis and Molecular Darwinism in Action: From Abiotic Generation of Nucleobases to Nucleosides and RNA

Molecular Darwinian evolution is an intrinsic property of reacting pools of molecules resulting in the adaptation of the system to changing conditions. It has no a priori aim. From the point of view of the origin of life, Darwinian selection behavior, when spontaneously emerging in the ensembles of molecules composing prebiotic pools, initiates subsequent evolution of increasingly complex and innovative chemical information. On the conservation side, it is a posteriori observed that numerous biological processes are based on prebiotically promptly made compounds, as proposed by the concept of Chemomimesis. Molecular Darwinian evolution and Chemomimesis are principles acting in balanced cooperation in the frame of Systems Chemistry. The one-pot synthesis of nucleosides in radical chemistry conditions is possibly a telling example of the operation of these principles. Other indications of similar cases of molecular evolution can be found among biogenic processes

Stability of 2′,3′ and 3′,5′ cyclic nucleotides in formamide and in water: a theoretical insight into the factors controlling the accumulation of nucleic acid building blocks in a prebiotic pool

International audienceSynthesis of the first RNAs represents one of the cornerstones of the emergence of life. Recent studies demonstrated powerful scenarios of prebiotic synthesis of cyclic nucleotides in aqueous and formamide environments. This raised a question about their thermodynamic stability, a decisive factor determining their accumulation in the prebiotic pool. Here we performed ab initio molecular dynamics simulations at various temperatures in formamide and water to study the relative stabilities of the 2',3' and 3',5' isomers of cyclic nucleotides. The computations show that in an aqueous environment 2',3' cyclic nucleotides are more stable than their 3',5' counterparts at all temperatures up to the boiling point. In contrast, in formamide higher temperatures favor accumulation of the 3',5' cyclic form, whereas below about 400 K the 2',3' cyclic form becomes more stable. The latter observation is consistent with a formamide-based origin scenario suggesting that 3',5' cyclic nucleotides accumulated at higher temperatures subsequently allowed oligomerization reactions after fast cooling to lower temperatures. A statistical analysis of the geometrical parameters of the solutes indicates that thermodynamics of cyclic nucleotides in aqueous and formamide environments are dictated by the floppiness of the molecules rather than by the ring strain of the cyclic phosphodiester linkages

Stereocontrolled Synthesis of (-)-Bactobolin A

A stereoselective synthesis of the ribosome-binding antitumor antibiotic (-)-bactobolin A is reported. The presented approach makes effective use of (-)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (-)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C-H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (-)-bactobolin A trifluoroacetate in 10% overall yield