Molecular: Systematic coarse grained modelling of DNA and proteins using the Newton Inversion method

The development of coarse-grained (CG) models of large biological molecules for efficient and accurate large scale molecular simulations is rapidly gaining increasing interest. Such simplified models allow studies across length and time scales not amenable at a detailed atomistic resolution. CG models not only reduce the amount of computing time but also the vast amount of data produced by atomistic simulations. The past decade has seen a blooming in the development of CG models of biomolecules, including lipids, proteins, or nucleic acids. Despite the plethora of published models, be it derived following an empirical or rigorous way, only a handful of them are tackling the DNA.
The goal of the project is to bring a deeper understanding of DNA structure/dynamics and their dependence on environmental conditions (salt concentration, temperature, ligands, binding proteins) and intrinsic characteristics (sequence, length, topology) by applying CG simulation methods on large scale complex systems comprising DNA and ions in solution. To construct our CG force fields (FFs), we rely on the Inverse Monte Carlo coarse-graining procedure, also known as Newton inversion and developed at Stockholm University by Profs. Lyubartsev and Laaksonen. The effective solvent-mediated pairwise interactions making up the CG FFs are obtained by inverting radial distribution functions and other particle-particle distributions obtained from long all-atom simulations of DNA containing systems.

Our CG FFs are suited for large-scale meso-scale simulations at micrometer microsecond scale using a wide spectrum of particle simulation methods from molecular dynamics to dissipative particle dynamics, as well as docking studies.

The questions to be addressed concern foreground themes such as sequence dependent structural and dynamical properties of DNA, DNA condensation and packaging, DNA repair and transcription regulation. Understanding DNA-protein interactions is of prominent importance as dysfunctions of the systems cited above are frequently associated with cancers. In addition to the fundamental aspects of such investigations, unraveling the intimate interplay between DNA and proteins is crucial to put new life in pharmaceutical research against cancer and the rational design of new drugs.

Newly published research paper:
Naômé, A.; Laaksonen, A.; Vercauteren, D. P. “A Solvent-Mediated Coarse-Grained Model of DNA Derived with the Systematic Newton Inversion Method” Journal of Chemical Theory and Computation, 2014, 10 (8), 3541–3549 (DOI: 10.1021/ct500222s)