Sequence dependent free energy profiles of localized B- to A-form transition of DNA in water

Abstract

DNA carries an inherent polymorphism, which surfaces under various external conditions. While B-form remains predominant under normal physiological conditions for most of the DNA sequences, low humidity and increased ion concentration cause B- to A-form transition. Certain proteins and molecules also sometimes cause local deformation of the DNA to the specific A-form. Previous experimental and computational studies focused on the overall B- to A-form transition. Here for the first time we investigated thermodynamics and mechanism of B- to A-form transition in water for various DNA sequences at a local dinucleotide base pair level. We introduced a new reaction coordinate Zp', based on the unique order parameter Zp, to drive B- to A-form transition locally and thereby calculate free energy profiles for the same for all the ten different dinucleotide steps embedded in a twelve base pair DNA. Results show that the trend of "A" and "B" philicity observed in experiment is preserved even at this local dinucleotide level, indicating its localized origin. Higher free energy cost obtained here is attributed to the cost of creating B∕A junctions along with formation of B->A transition at dimer level. We find that while water energetically stabilizes A-form for all the ten different dinucleotide steps to various extents, entropy acts against it. Therefore, we find that the stability of B-form DNA in water is entropic in origin. Mechanism of the conversion appears to be triggered by Slide; however, backbone parameters change concertedly.

Computational Approach to Explore the B/A Junction Free Energy in DNA

“…We have evidencef rom our earlier study [10] that free energy cost for B!At ransition along Zp' is much less compared to other available choices. Therefore, we recently proposed, [10] followingT sukuba'sc onvention, [21] its dynamicalv ersion Z 0 p .W ea lso showed that Z 0 p and Z p correlate well over severalc rystal structures. There are several parameters that define A-and B-form of DNA.…”

“…Based on the general Dickerson-Drew dodecamer [23] sequence d(CGCGAATTCGCG) 2 ,w eh ave designed twelve DNA sequences of 13 base pairs each, which can be described in general by d(CGCGXXYYYCGCG) 2 ,w here X/Y can be either A, T, C, or G. Reason for keeping the CG sequences in both termini is to reducet he chances of fraying at the ends. Note that in our previouss tudy, [10] all ten dinucleotide steps were flankedb y different steps. The p is the projection ofp on the unit vectorẑ.T he valueso fZ p and Z 0 p for the canonical A-and B-forms are shown.…”

“…The results are summarized in Figure 3, where we have plotted free energy difference, solvation energy difference,a nd stacking www.chemphyschem.org energy difference for B-A transition. [10] In case of CG andT Ts teps, the retarding effect of stacking energy is pronounced. [10] In case of CG andT Ts teps, the retarding effect of stacking energy is pronounced.…”

“…Surprisingly, the absolutef ree energy valuess uggest that CG is the most Bphilic step. [10] Experimental study of Frank-Kamenetskii [34] also suggested that B-DNA is primarily stabilized by stacking interactions and not by the hydrogen bonding between the bases. It is known from quantum mechanical calculations that CG has the most stabilizing stacking energy, [33] and opposes the B-A transition at al ocal level.…”

“…The amber99/parmbsc0 force field is well known to produce stable trajectories and, therefore, reliable to use in conformational exploration. [28] The reaction coordinates Z 0 p , [10] and Z 0 p were incorporated by us in PLUMED before patching to GROMACS. [28] The reaction coordinates Z 0 p , [10] and Z 0 p were incorporated by us in PLUMED before patching to GROMACS.…”