Modeling DNA deformations

Abstract

Recent developments have been made in modeling double-helical DNA at four levels of three-dimensional structure: the all-atom level, whereby an oligonucleotide duplex is surrounded by a shroud of solvent molecules; the base-pair level, with explicit backbone atoms; the mesoscopic level, that is, a few hundred base pairs, with the local duplex conformation described by knowledge-based harmonic energy functions; and the scale of several thousand nucleotides, with the duplex described as an ideal elastic rod. Predictions of the sequence-dependent bending and twisting of the double helix, as well as solvent- and force-induced B→A and over-stretching conformational transitions, are compared with experimental data. These subtle conformational changes are critical to the functioning of the double helix, including its packaging in the close confines of the cell, the mutual fit of DNA and protein in nucleoprotein complexes, and the effective recognition of base pairs in recombination and transcription.

Introduction

Molecular modeling is an integral part of contemporary structural biology. Almost all known structural information about DNA depends upon some level of molecular modeling. Except for the most highly resolved crystal structures determined to an accuracy of approximately 1 Å or better, all detailed X-ray and NMR representations of the double helix incorporate assumptions about chemical bonding and/or steric constraints in the refinement process. New methodological developments, which make it possible to crystallize and collect structural data for large DNA–protein assemblies, place even greater demands on molecular modeling in atomic reconstruction. The DNA wrapped around the core of histone proteins in the nucleosome [1] or the DNA distorted by proteins in the transcription assembly [2] presumably takes advantage of the intrinsic sequence-dependent features seen in the fine structures of isolated double helices [3^•]. Although there are growing numbers of well-resolved duplex structures, the known examples are isolated reference points on the conformational landscape traversed by DNA in the context of its biological processing. Understanding the structural transitions of the double helix, including its passage through the transiently ‘activated’ conformational states induced by enzymes and other molecular agents, is key to understanding the diverse biological roles of DNA. Modeling is thus an important part of the conception and analysis of both physicochemical and biological experiments.

The hierarchy of DNA structures, ranging from the chemical architecture of the nucleotide repeating unit to the large-scale folding and dynamics of the many thousands of base pairs (bp) packaged in chromatin, calls for a hierarchy of molecular models. This article highlights recent developments in the modeling of DNA structure at different levels of resolution. Space limitations preclude complete enumeration of the many articles on this subject published over the past two years. Instead, we present an in-depth discussion of a few topics that are illustrative of state-of-the-art modeling techniques and the understanding of DNA structure gleaned from such studies. For reasons of space, we restrict attention to the deformations and phase transitions of right-handed double-helical DNA that are likely to be involved in its biological recognition and processing. We also omit discussion of papers considered in recent reviews from this journal series 4, 5, 6, 7, 8.