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A coarse-grained model for assisting the investigation of structure and dynamics of large nucleic acids by ion mobility spectrometry–mass spectrometry

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Abstract

Ion Mobility Spectrometry–Mass Spectrometry (IMS-MS) is a rapidly emerging tool for the investigation of nucleic acid structure and dynamics. IMS-MS determinations can provide valuable information regarding alternative topologies, folding intermediates, and conformational heterogeneities, which are not readily accessible to other analytical techniques. The leading strategies for data interpretation rely on computational and experimental approaches to correctly assign experimental observations to putative structures. A very effective strategy involves the application of molecular dynamics (MD) simulations to predict the structure of the analyte molecule, calculate its collision cross section (CCS), and then compare this computational value with the corresponding experimental data. While this approach works well for small nucleic acid species, analyzing larger nucleic acids of biological interest is hampered by the computational cost associated with capturing their extensive structure and dynamics in all-atom detail. In this report, we describe the implementation of a coarse graining (CG) approach to reduce the cost of the computational methods employed in the data interpretation workflow. Our framework employs a five-bead model to accurately represent each nucleotide in the nucleic acid structure. The beads are appropriately parameterized to enable the direct calculation of CCS values from CG models, thus affording the ability to pursue the analysis of larger, highly dynamic constructs. The validity of this approach was successfully confirmed by the excellent correlation between the CCS values obtained in parallel by all-atom and CG workflows.

Graphical abstract: A coarse-grained model for assisting the investigation of structure and dynamics of large nucleic acids by ion mobility spectrometry–mass spectrometry

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Publication details

The article was received on 01 Feb 2017, accepted on 16 Mar 2017 and first published on 16 Mar 2017


Article type: Paper
DOI: 10.1039/C7CP00717E
Citation: Phys. Chem. Chem. Phys., 2017, Advance Article
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    A coarse-grained model for assisting the investigation of structure and dynamics of large nucleic acids by ion mobility spectrometry–mass spectrometry

    S. Vangaveti, R. J. D'Esposito, J. L. Lippens, D. Fabris and S. V. Ranganathan, Phys. Chem. Chem. Phys., 2017, Advance Article , DOI: 10.1039/C7CP00717E

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