Multiscale simulations of DNA from electrons to nucleosomes: 22 years of the Ascona B-DNA Consortium
CECAM-HQ-EPFL, Lausanne, Switzerland
DNA carries the genetic information an organism needs to develop, live and reproduce; and thus, processes such as transcription and replication are central to biology. However, DNA is a long, flexible, and structurally polymorphic molecule and its description is challenging due to its intrinsic multi-scale nature. Its multi-resolution high complexity requires modelling in an extremely wide range of sizes and time scales. During the last years, we have witnessed the development of a wide repertoire of theoretical methods that aimed to reproduce the properties of DNA, either isolated or protein-bound . These methods allow researchers to consider DNA at different resolution levels and provide knowledge of great value on its structure, dynamics, and interactions. Recently, this knowledge has broadened to encompass the idea that the detailed chemistry of the four canonical bases (plus their epigenetic modifications) also provide a sequence-dependent modulation of the physical properties of the DNA, such as nonzero intrinsic curvature, varying intrinsic twist, and variations in stiffness, and that these sequence-dependent variations of the physical properties of the DNA are actually key to the control and regulation of the biological processes involving the DNA. At a local scale, conformational changes in DNA are mediated by a complex choreography of backbone rearrangements that lead to local and global changes in the helix geometry [2,3] impacting the ability of the DNA to recognize ligands , and consequently on its functionality. Binding-induced conformational changes in DNA are required for function and are expected to follow the sequence-dependent intrinsic deformation modes of DNA, i.e. are implicitly coded in the spontaneous deformability of isolated DNA. Understanding the sequence-dependent physical properties of DNA then becomes crucial to rationalizing how ligands and, most notably nucleosomes, recognize and modulate DNA activity, i.e. the structural basis of gene regulation.
The Ascona B-DNA Consortium (ABC) initiative originated in 2001 at a conference in Monte Verità that involved a number of those working on methods and applications of Molecular Dynamics (MD) simulations to nucleic acids, and a second Ascona meeting was held in 2006. The original objective of the ABC project was to produce a database of state-of-the-art MD on DNA in which all 136 independent tetranucleotide steps were represented, developing standards and protocols for the simulation of DNA, and obtaining information for the comprehensive study and improved understanding of base-pair sequence effects on structure and dynamics . The ABC has been active during the last 20 years, involving more than 40 experts from Europe, Asia and America and dozens of collaborators focused on the structure of B-DNA from electrons and up to nucleosomes.
The ABC has published several key articles that rapidly became the gold standard in MD simulations of B-DNA, collecting hundreds of citations [3,5-9] and pushing the field to new paradigms. This year, the ABC started a new initiative with the aim to examine the sequence-dependent mechanical properties at the hexanucleotide level and the proposed meeting should be an opportunity to discuss the results of these very large-scale simulations and collaborative effort.
 P.D. Dans et al. (2016) Curr. Op. Struct. Biol. 37, 29-45.
 P.D. Dans et al. (2016) Nucl. Acids Res. 44, 4052-4066.
 M. Pasi et al. (2014) Nucl. Acids. Res. 42, 12272-12283.
 R. Rohs et al. (2010) Annu. Rev. Biochem 79, 233-269.
 D.L. Beveridge et al. (2012) J. Biosci. 37, 379–397.
 D.L. Beveridge et al. (2004) Biophys. J. 87, 3799-3813.
 S.B. Dixit et al. (2005) Biophys. J. 89, 3721-3740.
 R. Lavery et al. (2009) Nucl. Acids Res. 38, 299-313.
 P.D. Dans et al. (2019) Nucl. Acids Res. 47, 11090-11102.
Modesto Orozco (IRB Barcelona) - Organiser
John Maddocks (EPFL) - Organiser
Agnes Noy (University of York) - Organiser
Pablo D. Dans (University of the Republic) - Organiser