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 underphysiological conditions However it adopts a short and compact A DNA form underdehydrating conditions The proteins such as polymerases endonucleases etc ofteninteract with a small segment of DNA causing local A DNA formation The effectivemechanism of B DNA to A DNA transition is sequence dependent and arises frommultiple dinucleotide steps interacting with each other We have employed enhancedsampling simulations to explore the thermodynamics and mechanistic details of 10unique dinucleotide steps undergoing B to A transition in aqueous environment Inour work the heterogeneous B to A transition mechanism of dinucleotide steps androle of solvent portrayed sequence dependency of the transition The study is furtherextended to calculate the B form A form interface or junction free energy andeventually the 8220 absolute 8221 free energy values which are the free energy estimates ofB 56256 56431 A transition of a dinucleotide step uninfluenced by the flanking base pairs Apredictive model for the conformational preference of a nucleotide sequence towardsA or B form is developed based on the absolute free energy values for 10 uniquedinucleotide steps There are only a few models existing with such predictivecapability and our model shows better accuracy than the existing ones We applied themodel successfully to discover unknown A DNA promoter sequences APS ingenome The reliability of our proposed method is established through experimentalverification Finally we studied the global whole DNA B to A DNA transition of asingle DNA helix in solution which showed the existence of a multistep non classicalnucleation mechanism for B to A transition for the first time newline newline