Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex

Abstract Base pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale ther...

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Autores principales:	Yogeeshwar Ajjugal, Kripi Tomar, D. Krishna Rao, Thenmalarchelvi Rathinavelan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f56e1711fedf49b7ba866dfbf635bfb5
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spelling	oai:doaj.org-article:f56e1711fedf49b7ba866dfbf635bfb52021-12-02T13:30:34ZSpontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex10.1038/s41598-021-82669-42045-2322https://doaj.org/article/f56e1711fedf49b7ba866dfbf635bfb52021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82669-4https://doaj.org/toc/2045-2322Abstract Base pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale thermophoresis (MST) and NMR techniques. MD simulations reveal that the A…A mismatch experiences several transient events such as base flipping, base extrusion, etc. facilitating B–Z junction formation. A…A mismatch may assume such conformational transitions to circumvent the effect of nonisostericity with the flanking canonical base pairs so as to get accommodated in the DNA. CD and 1D proton NMR experiments further reveal that the extent of B–Z junction increases when the number of A…A mismatch in d(CAA)·d(T(A/T)G) increases (1–5). CD titration studies of d(CAA)·d(TAG)n=5 with the hZαADAR1 show the passive binding between the two, wherein, the binding of protein commences with B–Z junction recognition. Umbrella sampling simulation indicates that the mismatch samples anti…+ syn/+ syn…anti, anti…anti & + syn…+ syn glycosyl conformations. The concomitant spontaneous transitions are: a variety of hydrogen bonding patterns, stacking and minor or major groove extrahelical movements (with and without the engagement of hydrogen bonds) involving the mismatch adenines. These transitions frequently happen in anti…anti conformational region compared with the other three regions as revealed from the lifetime of these states. Further, 2D-NOESY experiments indicate that the number of cross-peaks diminishes with the increasing number of A…A mismatches implicating its dynamic nature. The spontaneous extrahelical movement seen in A…A mismatch may be a key pre-trapping event in the mismatch repair due to the accessibility of the base(s) to the sophisticated mismatch repair machinery.Yogeeshwar AjjugalKripi TomarD. Krishna RaoThenmalarchelvi RathinavelanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yogeeshwar Ajjugal Kripi Tomar D. Krishna Rao Thenmalarchelvi Rathinavelan Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex
description	Abstract Base pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale thermophoresis (MST) and NMR techniques. MD simulations reveal that the A…A mismatch experiences several transient events such as base flipping, base extrusion, etc. facilitating B–Z junction formation. A…A mismatch may assume such conformational transitions to circumvent the effect of nonisostericity with the flanking canonical base pairs so as to get accommodated in the DNA. CD and 1D proton NMR experiments further reveal that the extent of B–Z junction increases when the number of A…A mismatch in d(CAA)·d(T(A/T)G) increases (1–5). CD titration studies of d(CAA)·d(TAG)n=5 with the hZαADAR1 show the passive binding between the two, wherein, the binding of protein commences with B–Z junction recognition. Umbrella sampling simulation indicates that the mismatch samples anti…+ syn/+ syn…anti, anti…anti & + syn…+ syn glycosyl conformations. The concomitant spontaneous transitions are: a variety of hydrogen bonding patterns, stacking and minor or major groove extrahelical movements (with and without the engagement of hydrogen bonds) involving the mismatch adenines. These transitions frequently happen in anti…anti conformational region compared with the other three regions as revealed from the lifetime of these states. Further, 2D-NOESY experiments indicate that the number of cross-peaks diminishes with the increasing number of A…A mismatches implicating its dynamic nature. The spontaneous extrahelical movement seen in A…A mismatch may be a key pre-trapping event in the mismatch repair due to the accessibility of the base(s) to the sophisticated mismatch repair machinery.
format	article
author	Yogeeshwar Ajjugal Kripi Tomar D. Krishna Rao Thenmalarchelvi Rathinavelan
author_facet	Yogeeshwar Ajjugal Kripi Tomar D. Krishna Rao Thenmalarchelvi Rathinavelan
author_sort	Yogeeshwar Ajjugal
title	Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex
title_short	Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex
title_full	Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex
title_fullStr	Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex
title_full_unstemmed	Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex
title_sort	spontaneous and frequent conformational dynamics induced by a…a mismatch in d(caa)·d(tag) duplex
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f56e1711fedf49b7ba866dfbf635bfb5
work_keys_str_mv	AT yogeeshwarajjugal spontaneousandfrequentconformationaldynamicsinducedbyaamismatchindcaadtagduplex AT kripitomar spontaneousandfrequentconformationaldynamicsinducedbyaamismatchindcaadtagduplex AT dkrishnarao spontaneousandfrequentconformationaldynamicsinducedbyaamismatchindcaadtagduplex AT thenmalarchelvirathinavelan spontaneousandfrequentconformationaldynamicsinducedbyaamismatchindcaadtagduplex
_version_	1718392951080484864

Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex

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