Basics of Nucleic Acid Structure:Concepts, Tools, and Archives.- Using Amber to simulate DNA and RNA.- Theoretical Studies of Nucleic Acids and Nucleic Acid-Protein Complexes Using CHARMM.- Continuum Solvent Models to Study the Structure and Dynamics of Nucleic Acids and Complexes With Ligands.- Data Mining of Molecular Dynamic Trajectories of Nucleic Acids.- Enhanced Sampling Methods for Atomistic Simulation Of Nucleic Acids.- Modeling DNA Deformation.- Molecular Dynamics Simulations and Free Energy Calculations on Protein-Nucleic Acid Complexes.- DNA Simulation Benchmarks as Revealed by X-Ray Structures.-RNA: The Cousin Left Behind Becomes a Star.- Molecular dynamics simulations of RNA systems: importance of the initial conditions- RNA molecular dynamics.- Molecular dynamics simulations of nucleic acids: MD simulations of G-DNA and functional RNAs.- Using Computer Simulations to Study Decoding by the Ribosome.- Base stacking and base pairing: Advanced quantum chemical studies.- Interaction of Metal Cations With Nucleic Acids and their Building Units: A comprehensive view from quantum chemical calculations.- Proton transfer in DNA base pairs: Potential mutagenic processes.- Comparative Study of Quantum Mechanical Methods Related to Nucleic Acid Bases: Electronic Spectra, Excited State Structures and Interactions.- Substituent Effects on Hydrogen Bonds in DNA:A Kohn-Sham DFT approach.- Computational modeling of charge transfer in DNA.- Quantum chemical calculations of NMR parameters.- The Importance of Entropic Factors In DNA Behaviour: Insights From Simulations.- Sequence-dependent harmonic deformability of nucleic acids inferred from atomistic molecular dynamics.- Simulation of equilibrium and dynamic properties of large DNA molecules.- Chromatin Simulations: From DNA to chromatin fibers.
Chapter 7 MODELING DNA DEFORMATION (p. 169-170)
Péter Várnai1,2 and Richard Lavery11Laboratoire de Biochimie Théorique, CNRS UPR 9080, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, Paris 75005, France
2University of Cambridge,Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, United Kingdom
Abstract: Deformations of DNA contribute to its essential biological function. In our laboratory, we have been studying both local and global deformations of DNA and their relationship to base sequence by molecular modeling and simulation techniques. In the current chapter, we first give an overview of the various approaches used in our laboratory to build DNA models and to control DNA deformations. Notably, we discuss the JUMNA program that uses internal and helicoidal variables, and also umbrella sampling free energy simulations used to follow DNA deformations. In the second part, we summarize the results these techniques enabled us to obtain, starting from the large scale deformations, such as stretching, twisting and bending, down to the more local changes involving base opening and flipping and backbone conformations. A separate section deals with the sequence specific recognition of DNA by proteins and the role of DNA deformation in the process. We hope to show the reader that theoretical studies can play a significant role in obtaining a better understanding of this fascinating biopolymer.
Key words: DNA deformation, recognition, base flipping, single molecule manipulation, internal coordinates, JUMNA, AMBER, umbrella sampling, free energy, MMPBSA
1. DNA DEFORMATION AND ITS BIOLOGICAL INTEREST
At first sight, DNA seems to be a relatively simple biopolymer. While it is a heteropolymer, it is composed of only four different nucleotides, a small number compared to the 20 amino acids which constitute the polypeptide chain of proteins. This simplicity led early researchers to initially reject DNA as the potential carrier of genetic information. While the beautiful double helical structure proposed by Watson and Crick1,2 and the subsequent discovery of the triplet genetic code,3,4 explained how DNA could stock enormous amounts of information, it again suggested that structurally there was not much to study. At the core of the double helical structure was the observation that the spiral phosphodiester backbones could accommodate any Watson-Crick base pair sequence without deformation.
The first step to refining this viewpoint comes from realizing that DNA must be packed quite densely to fit into a cell. This is easily illustrated in the case of human cells which contain around 1 m of DNA (corresponding to 4 x 109 base pairs) in a nucleus within a diameter of only a few microns. Within sperm heads, the packing density is even higher. A partial explanation of how this is achieved comes from modeling DNA as a flexible rod, which naturally forms a random coil to increase its conformational entropy. But this factor alone only is not enough to account for the packing that occurs within the nucleus. As we now know, the remainder is due to protein-induced superhelical compaction leading to the complex and hierarchical structure of chromatin.
A second type of deformation was detected early in the study of DNA and concerns its overall helical form. Fiber diffraction studies already showed that the double helical structure could be modified as a function of its solvent and counterion environment. The A and B forms of the double helix first named by Rosalind Franklin5 are now structurally well-characterized and they have been joined by many other conformational families which go even further in tampering with DNA structure, by modifying its helical chirality, changing its number of strands, its base pairing and its relative strand orientations. In recent years, structural studies have been joined by single molecule manipulation experiments which offer us a new way to directly probe the mechanical properties of DNA.6 These experiments have again showed that DNA is more complex than initially expected and that, when pulled or twisted, it can undergo transitions to new and unexpected conformations.
