Theoretical Study of B-DNA to A-DNA Transition: From Local Dinucleotide Step to Global Helical Conversion

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.