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Melting temperature measurement and mesoscopic evaluation of single, double and triple DNA mismatches

Melting temperature measurement and mesoscopic evaluation of single, double and triple DNA mismatches
Melting temperature measurement and mesoscopic evaluation of single, double and triple DNA mismatches
Unlike the canonical base pairs AT and GC, the molecular properties of mismatches such as hydrogen bonding and stacking interactions are strongly dependent on the identity of the neighbouring base pairs. As a result, due to the sheer number of possible combinations of mismatches and flanking base pairs, only a fraction of these have been studied in varying experiments or theoretical models. Here, we report on the melting temperature measurement and mesoscopic analysis of contiguous DNA mismatches in nearest-neighbours and next-nearest neighbour contexts. A total of 4032 different mismatch combinations, including single, double and triple mismatches were covered. These were compared with 64 sequences containing all combinations of canonical base pairs in the same location under the same conditions. For a substantial number of single mismatch configurations, 15%, the measured melting temperatures were higher than the least stable AT base pair. The mesoscopic calculation, using the Peyrard–Bishop model, was performed on the set of 4096 sequences, and resulted in estimates of on-site and nearest-neighbour interactions that can be correlated to hydrogen bonding and base stacking. Our results confirm many of the known properties of mismatches, including the peculiar sheared stacking of tandem GA mismatches. More intriguingly, it also reveals that a number of mismatches present strong hydrogen bonding when flanked on both sites by other mismatches. To highlight the applicability of our results, we discuss a number of practical situations such as enzyme binding affinities, thymine DNA glycosylase repair activity, and trinucleotide repeat expansions.
2041-6520
8273-8287
Oliveira, Luciana M.
7a7f4da3-9f8c-4e2c-97e6-cde375c69930
Long, Adam S.
62130959-63bb-4ae2-92a6-4664aba7e893
Brown, Tom
a64aae36-bb30-42df-88a2-11be394e8c89
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Weber, Gerald
7cfc4eb7-a658-44fd-97e3-b3be79a6615f
Oliveira, Luciana M.
7a7f4da3-9f8c-4e2c-97e6-cde375c69930
Long, Adam S.
62130959-63bb-4ae2-92a6-4664aba7e893
Brown, Tom
a64aae36-bb30-42df-88a2-11be394e8c89
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Weber, Gerald
7cfc4eb7-a658-44fd-97e3-b3be79a6615f

Oliveira, Luciana M., Long, Adam S., Brown, Tom, Fox, Keith R. and Weber, Gerald (2020) Melting temperature measurement and mesoscopic evaluation of single, double and triple DNA mismatches. Chemical Science, 11 (31), 8273-8287. (doi:10.1039/D0SC01700K).

Record type: Article

Abstract

Unlike the canonical base pairs AT and GC, the molecular properties of mismatches such as hydrogen bonding and stacking interactions are strongly dependent on the identity of the neighbouring base pairs. As a result, due to the sheer number of possible combinations of mismatches and flanking base pairs, only a fraction of these have been studied in varying experiments or theoretical models. Here, we report on the melting temperature measurement and mesoscopic analysis of contiguous DNA mismatches in nearest-neighbours and next-nearest neighbour contexts. A total of 4032 different mismatch combinations, including single, double and triple mismatches were covered. These were compared with 64 sequences containing all combinations of canonical base pairs in the same location under the same conditions. For a substantial number of single mismatch configurations, 15%, the measured melting temperatures were higher than the least stable AT base pair. The mesoscopic calculation, using the Peyrard–Bishop model, was performed on the set of 4096 sequences, and resulted in estimates of on-site and nearest-neighbour interactions that can be correlated to hydrogen bonding and base stacking. Our results confirm many of the known properties of mismatches, including the peculiar sheared stacking of tandem GA mismatches. More intriguingly, it also reveals that a number of mismatches present strong hydrogen bonding when flanked on both sites by other mismatches. To highlight the applicability of our results, we discuss a number of practical situations such as enzyme binding affinities, thymine DNA glycosylase repair activity, and trinucleotide repeat expansions.

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d0sc01700k - Version of Record
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Accepted/In Press date: 23 July 2020
e-pub ahead of print date: 23 July 2020
Published date: 21 August 2020

Identifiers

Local EPrints ID: 442926
URI: http://eprints.soton.ac.uk/id/eprint/442926
ISSN: 2041-6520
PURE UUID: a7dacd94-84f0-4db2-b586-098809e9b0e4
ORCID for Keith R. Fox: ORCID iD orcid.org/0000-0002-2925-7315

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Date deposited: 31 Jul 2020 16:33
Last modified: 18 Feb 2021 16:35

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Contributors

Author: Luciana M. Oliveira
Author: Adam S. Long
Author: Tom Brown
Author: Keith R. Fox ORCID iD
Author: Gerald Weber

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