Free energy landscape and transition pathways from Watson-Crick to Hoogsteen base pairing in free duplex DNA.

Changwon Yang,Youngshang Pak,Eunae Kim

doi:10.1093/nar/gkv796

Changwon Yang, Youngshang Pak + Show 1 more

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https://doi.org/10.1093/nar/gkv796

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Abstract

Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson–Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine–thymine (A–T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events.

Highlights

The inherent flexibilities of double helical DNAs facilitate spontaneous conformational fluctuations, which induce base pairs to adopt different geometries other than those dictated by the conventional Watson–Crick (WC) base pairing
Since changes in these parameters were limited to only the ribonucleic acids (RNA) bases, we proposed to apply these parameters to the bases of duplex DNA
Detailed transition mechanism between the WC and HG bp in a naked DNA can provide a molecular basis for elucidating inherent functions of duplex DNAs beyond their genetic codes

Summary

Introduction

The inherent flexibilities of double helical DNAs facilitate spontaneous conformational fluctuations, which induce base pairs (bps) to adopt different geometries other than those dictated by the conventional Watson–Crick (WC) base pairing. Nikolova et al were able to trap the HG bp in free adenine–thymine (A–T) rich DNA duplexes [12] They showed that this alternative bp can exist as transient entities in thermal equilibrium with the WC bp and that for example lifetimes of the transient HG bp state of A6DNA are 0.3 ms for A–T pair and 1.5 ms for G–C pair (See Figure 1B for the sequence of A6-DNA). This finding is of great importance, because it shows that a free double helical DNA has an intrinsic ability to modulate its function by undergoing a spontaneous conformational switch between WC and HG bps. Earlier NMR studies significantly advanced our understanding of the dynamics and thermodynamic stability of the HG bp state by measuring transition rates and equilibrium constants between the WC and HG bp states, detailed pathways for these bp transitions have not been resolved experimentally

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