Analyzing
the Relationship between Single Base Flipping
and Strand Slippage near DNA
Duplex Termini
- Publication date
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Abstract
Insertion–deletion (indel)
mutations are caused by strand
slippage between pairing primer and template strands during nucleic
acid strand extension. A possible causative factor for such strand
slippage is base flipping in the primer strand or template strand,
for insertion or deletion mutations, respectively. A simple mechanistic
description is that the “hole” in the nucleic acid duplex
left behind by a flipping base is occupied by a neighboring base on
the same strand, resulting in slippage with respect to its paired
strand. The extent of single base flipping required for occupation
of its former place in the double helix by a neighboring base is not
fully understood. The present study uses restrained molecular dynamics
(MD) simulations along a pseudohedihedral base flipping parameter
to construct two-dimensional free energy profiles along base flipping
and strand slippage geometric parameters. These profiles, generated
for both cytosine and guanine single base flipping in a short repetitive
indel mutation hot-spot DNA sequence, illustrate the extent of single
base flipping that can allow strand slippage by one base position.
Relatively minor base flipping into both the major and minor grooves
can result in strand slippage. Deconstruction of the collective variable
strand slippage geometric parameter into its component distances illustrates
the details of how strand slippage can accompany base flipping. The
trans Watson–Crick:sugar edge interaction that stabilizes cytosine
flipping in this hot-spot sequence is also characterized energetically.
The impact of these results on understanding sequence dependence of
indel errors in nucleic acid strand extension is discussed, along
with a suggestion for future studies that can generalize the present
findings to all nearest-neighbor sequence contexts