The static and dynamic structural heterogeneities of B-DNA: extending Calladine-Dickerson rules.

Pablo D Dans,Alessandro S Patelli,Modesto Orozco,Marco Pasi,Alexandra Balaceanu,Richard Lavery,Daiva Petkevičiūtė,Jürgen Walther,Adam Hospital,John H Maddocks,Genís Bayarri

doi:10.1093/nar/gkz905

Abstract

We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent for certain tetranucleotide sequence contexts and are always coupled to a complex network of coordinated changes in the backbone. The analysis of our simulations, which contain instances of all tetranucleotide sequences, allow us to extend Calladine–Dickerson rules used for decades to interpret the average geometry of DNA, leading to a set of rules with quantitative predictive power that encompass nonlocal sequence-dependence and anharmonic fluctuations.

Highlights

DNA is a flexible and structurally polymorphic polymer whose overall equilibrium geometry strongly depends on its sequence, the solvent environment, and the presence of ligands [1,2]
The analysis of numerous molecular dynamics trajectories obtained with an accurate, last generation, force field has allowed us to derive some general rules concerning the equilibrium conformation distribution of B-DNA, which represent a significant step beyond Calladine–Dickerson earlier propositions
The first and second moments of the equilibrium distributions of helical coordinates for DNA can only be understood in terms of nonlocal sequence-dependence contexts, to at least the trinucleotide level for intra-basepair coordinates, and the tetranucleotide level for inter-basepair coordinates

Summary

Introduction

DNA is a flexible and structurally polymorphic polymer whose overall equilibrium geometry strongly depends on its sequence, the solvent environment, and the presence of ligands [1,2]. Conformational changes in DNA are mediated by a complex choreography of backbone rearrangements such as the BI/BII transition [3,4], the low-twist/high-twist equilibrium [5,6], or concerted ␣/␥ rotations [7,8,9] Such backbone rearrangements lead to local and global changes in the helix geometry [9,10] impacting on the ability of the DNA to recognize ligands [11], and on its functionality. Binding-induced conformational changes in DNA are required for function and are expected to follow the sequencedependent intrinsic deformation modes of DNA, i.e. are implicitly coded in the spontaneous deformability of isolated DNA This suggests that evolution has refined DNA sequence to maximize ligand-DNA interactions and to reduce the energetic cost of moving from a canonical to a bioactive conformation [11,12].

Methods

Results

Conclusion