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Importance of Anion-π Interactions in RNA GAAA and GGAG Tetraloops: A Combined MD and QM Study.

ABSTRACT: In this study, we demonstrate that anion-π interactions (an attractive noncovalent force between electron deficient π-systems and anions) are involved in the stabilization of GAAA and GGAG RNA tetraloops. Using the single recognition particle (SRP)-RNA complexes as a case of study, we combined molecular dynamics (MD) and quantum mechanics (QM) calculations to shed light on the structural influence of phosphate-G anion-π interactions and hydrogen bonds (HBs) involving K⁺/Mg²⁺ water clusters. In addition, the RNA assemblies herein were further characterized by means of the "atoms in molecules" (AIM) and noncovalent interactions plot (NCIplot) methodologies. We believe the results derived from this study might be important in the fields of chemical biology (RNA folding and engineering) and supramolecular chemistry (anion-π interactions) as well as to further expand the current knowledge regarding RNA structural motifs.

SUBMITTER: Esmaeeli R

PROVIDER: S-EPMC8515804 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Importance of Anion-π Interactions in RNA GAAA and GGAG Tetraloops: A Combined MD and QM Study.

Esmaeeli Reza R Piña María de Las Nieves MLN Frontera Antonio A Pérez Alberto A Bauzá Antonio A

Journal of chemical theory and computation 20210929 10

In this study, we demonstrate that anion-π interactions (an attractive noncovalent force between electron deficient π-systems and anions) are involved in the stabilization of GAAA and GGAG RNA tetraloops. Using the single recognition particle (SRP)-RNA complexes as a case of study, we combined molecular dynamics (MD) and quantum mechanics (QM) calculations to shed light on the structural influence of phosphate-G anion-π interactions and hydrogen bonds (HBs) involving K<sup>+</sup>/Mg<sup>2+</sup ...[more]

PMID: 34586810

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Project description:The synthesis of oligosaccharides and other carbohydrate derivatives is of relevance for the advancement of glycosciences both at the fundamental and applied level. For many years, glycosyl hydrolases (GHs) have been explored to catalyze the synthesis of glycosidic bonds. In particular, retaining GHs can catalyze a transglycosylation (T) reaction that competes with hydrolysis (H). This has been done either employing controlled conditions in wild type GHs or by engineering new mutants. The goal, which is to increase the T/H ratio, has been achieved with moderate success in several cases despite the fact that the molecular basis for T/H modulation are unclear. Here we have used QM(DFT)/MM calculations to compare the glycosylation, hydrolysis and transglycosylation steps catalyzed by wild type Thermus thermophilus β-glycosidase (family GH1), a retaining glycosyl hydrolase for which a transglycosylation yield of 36% has been determined experimentally. The three transition states have a strong oxocarbenium character and ring conformations between 4H3 and 4E. The atomic charges at the transition states for hydrolysis and transglycosylation are very similar, except for the more negative charge of the oxygen atom of water when compared to that of the acceptor Glc. The glycosylation transition state has a stronger S N 2 character than the deglycosylation ones and the proton transfer is less advanced. At the QM(PBE0/TZVP)/MM level, the TS for transglycosylation has shorter O4GLC-C1FUC (forming bond) distance and longer OE2GLU338-C1FUC (breaking) distance than the hydrolysis one, although the HACC proton is closer to the Glu164 base in the hydrolysis TS. The QM(SCC-DFTB)/MM free energy maxima show the inverted situation, although the hydrolysis TS presents significant structural fluctuations. The 3-OHGLC group of the acceptor Glc (transglycosylation) and WAT432 (neighbor water in hydrolysis) are identified to stabilize the oxocarbenium transition states through interaction with O5FUC and O4FUC. The analysis of interaction suggests that perturbing the Glu392-Fuc interaction could increase the T/H ratio, either by direct mutation of this residue or indirectly as reported experimentally in the Asn390I and Phe401S cases. The molecular understanding of similarities and differences between hydrolysis and transglycosylation steps may be of help in the design of new biocatalysts for glycan synthesis.

Dataset Information

Importance of Anion-π Interactions in RNA GAAA and GGAG Tetraloops: A Combined MD and QM Study.

Publications

Importance of Anion-π Interactions in RNA GAAA and GGAG Tetraloops: A Combined MD and QM Study.

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