Abstract:
The biological polyanionic polymer, DNA adopts canonical B-form under
physiological conditions. However, it adopts a short and compact A-DNA form under
dehydrating conditions. The proteins such as polymerases, endonucleases, etc. often
interact with a small segment of DNA causing local A-DNA formation. The effective
mechanism of B-DNA to A-DNA transition is sequence dependent and arises from
multiple dinucleotide steps interacting with each other. We have employed enhanced
sampling simulations to explore the thermodynamics and mechanistic details of 10
unique dinucleotide steps undergoing B to A transition in aqueous environment. In
our work, the heterogeneous B to A transition mechanism of dinucleotide steps and
role of solvent portrayed sequence dependency of the transition. The study is further
extended to calculate the B-form/A-form interface or junction free energy and
eventually, the “absolute” free energy values, which are the free energy estimates of
B A transition of a dinucleotide step uninfluenced by the flanking base pairs. A
predictive model for the conformational preference of a nucleotide sequence towards
A- or B-form is developed based on the absolute free energy values for 10 unique
dinucleotide steps. There are only a few models existing with such predictive
capability and our model shows better accuracy than the existing ones. We applied the
model successfully to discover unknown A-DNA promoter sequences (APS) in
genome. The reliability of our proposed method is established through experimental
verification. Finally, we studied the global (whole DNA) B to A DNA transition of a
single DNA helix in solution which showed the existence of a multistep non-classical
nucleation mechanism for B to A transition for the first time.
