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However, mesoscopic models have a comparable numerical efficiency to NN models, yet can provide details on intramolecular interactions. For instance the nearest-neighbour (NN) model is simple enough to be numerically efficient, but does not provide the desired level of structural information. These models need to be computationally efficient which requires a considerable level of simplification.
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Few theoretical models can deal simultaneously with the large amount of sequences that would cover that many mismatch contexts. 16–18Įvaluating the dependence of the thermal and structural properties of mismatches with nearly all possible nearest neighbours, which we will refer to as the context, is a challenging problem. For instance, the thymine excision efficiency of GT mismatches, due to thymine-DNA glycosylase, has a well known dependency on the type of base-pairs neighbouring GT. 14,15 Similarly, mismatch repair may depend on the type of flanking base pair. 13 In most cases, the efficiency of mismatch recognition depends strongly on the type of mismatch as well as on its neighbouring base pairs. 12 Furthermore, mismatch recognition can be performed by a substantial number of small organic molecules and metal complexes with the potential for acting as drugs. 11 Mismatch recognition is also known to be important for base pair substitution in Cas9-induced DNA breaks. A central aspect for repairing a mismatch defect is its recognition by specialized enzymes such as MutS, 6–8 Msh2–Msh6, 9,10 and Rad4/XPC. 5 However, if left uncorrected they give rise to mutations. 4 When they do occur, they are checked and corrected by an extensive array of repair mechanisms. Mismatches can occur in genomic DNA and are produced by a range of factors, such as replication errors, 2 misincorporation 3 and cytosine methylation. To date there is still no study that considers all mismatch configurations under the same conditions. The properties of mismatches are very sensitive to experimental conditions such as pH and salt concentrations, which further complicates comparative studies. The situation with two or three consecutive mismatches becomes even more complicated and even fewer of these possible configurations have been studied.
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1 As a result, the number of configuration dependent properties is very large and to date only a few of these have been analysed experimentally or theoretically. In contrast, there are eight additional mismatched base-pair combinations, namely AA, AC, AG, CC, CT, GG, GT and TT and, unlike canonical base pairs, their properties depend strongly on their nearest-neighbour configurations. As a consequence, the number of different interactions of canonical base pairs is fairly small and it is relatively simple to construct efficient thermodynamic models. The stacking interaction strength between nearest-neighbours is also largely independent of next-nearest-neighbours. Introduction The hydrogen bonding strength of canonical AT and GC base pairs in duplex DNA is essentially independent of the flanking base pairs. 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. More intriguingly, it also reveals that a number of mismatches present strong hydrogen bonding when flanked on both sites by other mismatches. Our results confirm many of the known properties of mismatches, including the peculiar sheared stacking of tandem GA mismatches. 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. For a substantial number of single mismatch configurations, 15%, the measured melting temperatures were higher than the least stable AT base pair. These were compared with 64 sequences containing all combinations of canonical base pairs in the same location under the same conditions. A total of 4032 different mismatch combinations, including single, double and triple mismatches were covered. Here, we report on the melting temperature measurement and mesoscopic analysis of contiguous DNA mismatches in nearest-neighbours and next-nearest neighbour contexts.
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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. 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.