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Probing RNA Structure with Dimethyl Sulfate Mutational Profiling with Sequencing In Vitro and in Cells
Published on: December 9, 2022
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Characterizing 3D RNA structural features from DMS reactivity
D H Sanduni Deenalattha1, Chris P Jurich1, Bret Lange1
1Department of Chemistry, University of Nebraska, 639 North 12 St, Lincoln, NE 68588, USA.
Biorxiv : the Preprint Server for Biology
|November 28, 2024
Summary
Dimethyl sulfate (DMS) chemical mapping reveals RNA structure nuances. Deviations from standard Watson-Crick base pairing rules in DMS reactivity offer insights into complex RNA 3D conformations and dynamics.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- Dimethyl sulfate (DMS) is a chemical probe used to study RNA structure.
- DMS reactivity typically indicates nucleotide accessibility: low reactivity suggests Watson-Crick (WC) base pairs, while high reactivity implies unpaired nucleotides.
- Previous studies noted exceptions to this rule, but the frequency and structural basis of these outliers were not fully understood.
Purpose of the Study:
- To systematically analyze DMS reactivity patterns in a large dataset of RNA structures.
- To identify recurring 3D structural features associated with non-canonical DMS reactivity.
- To explore the potential of DMS reactivity for detailed RNA structure and dynamics modeling.
Main Methods:
- Systematic analysis of DMS reactivity data from 7,500 RNA constructs with known 3D structures.
- Correlation of DMS reactivity values with base pairing status (WC vs. non-WC), solvent accessibility, hydrogen bonding, base stacking, and junction dynamics.
- Investigation of DMS reactivity in non-canonical pairs against atomic distances and base pair geometry.
Main Results:
- DMS reactivity spans four orders of magnitude, with a ~10% overlap between WC and non-WC nucleotides.
- Non-WC bases with protected DMS reactivity showed increased hydrogen bonding and reduced solvent accessibility.
- WC pairs with higher DMS reactivity were often located at junctions, associated with weaker base stacking and increased dynamics.
- DMS reactivity in non-canonical pairs correlated with geometric parameters, allowing discrimination of 3D conformations.
Conclusions:
- DMS chemical mapping provides atomic-scale resolution of RNA 3D structures beyond simple base-pairing status.
- Deviations in DMS reactivity are linked to specific structural features like hydrogen bonding, solvent accessibility, and junction dynamics.
- DMS reactivity patterns can be leveraged to build more accurate models of RNA structure and dynamics.
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