Relative Flexibility of DNA and RNA: a Molecular Dynamics Study Agnes Noy 1 , Alberto Pe ´rez 1 , Filip Lankas 2 , F. Javier Luque 3 and Modesto Orozco 1,4 * 1 Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biome `dica, Parc Cientı ´fic de Barcelona, Josep Samitier 1-5, Barcelona 08028 Spain 2 Bernoulli Institute for Mathematics, EPFL (Swiss Federal Polytechnical Institute) 1015 Lausanne, Switzerland 3 Departament de Fisicoquı ´mica Facultat de Farma `cia Universitat de Barcelona Avgda Diagonal 643, Barcelona 08028, Spain 4 Departament de Bioquı ´mica i Biologia Molecular, Facultat de Quı ´mica, Universitat de Barcelona, Martı ´ i Franque `s 1 Barcelona 08028, Spain State of the art molecular dynamics simulations are used to study the structure, dynamics, molecular interaction properties and flexibility of DNA and RNA duplexes in aqueous solution. Special attention is paid to the deformability of both types of structures, revisiting concepts on the relative flexibility of DNA and RNA duplexes. Our simulations strongly suggest that the concepts of flexibility, rigidity and deformability are much more complex than usually believed, and that it is not always true that DNA is more flexible than RNA. q 2004 Elsevier Ltd. All rights reserved. Keywords: DNA; RNA; flexibility; molecular dynamics; similarity indexes *Corresponding author Introduction Under physiological conditions DNA exists as an elongated helix known as B-form, while if possible RNA forms a double helix more compact than that of DNA, 1–3 which is named the A-form. The different puckering of sugars in B (South to South- East) and A (North) forms alters the structure of the grooves, 1–4 which changes completely the ability of the nucleic acids to interact with other molecules, particularly with proteins. 1–3 It seems the different helical structure of DNA and RNA might determine their different role in the cell. However, structure itself is not able to explain the incredible ability of proteins to distinguish between nucleic acid struc- tures. For example, only a fraction of very similar structural distortions of DNA are recognized by the UvABC excision repair mechanism. 1–3,5 Indeed, it is known that RNase H recognizes and degrades DNA–RNA hybrids, but it is inactive against RNA– RNA duplexes and other RNA-hybrid molecules, despite the fact that all these duplexes pertain to the A-family. 6,7 More surprisingly, the complex mecha- nism involving gene silencing by small interference RNAs is activated by duplex RNA, but not by other RNA hybrid duplexes of similar structure. 8,9 Clearly, besides the general helical structure, other properties must be exploited by nature to dis- tinguish between helical structures. RNA adopts very unique conformations in the cell, like those of ribozymes, transfer or ribosomal RNAs. However, it is believed that this is mostly due to the fact that cellular RNA is single-stranded and intramolecular RNA duplexes contain unpaired bases and mismatches which favour strong twists and kinks in the helix. However, it is generally accepted in the scientific community that the DNA double helix is more flexible than the RNA one. This assumption is supported by indirect low resolution experimental data 10,11 like that derived 0022-2836/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. Abbreviations used: MD, molecular dynamics; RMSD, root mean square deviations. E-mail address of the corresponding author: modesto@mmb.pcb.ub.es doi:10.1016/j.jmb.2004.07.048 J. Mol. Biol. (2004) 343, 627–638