Frontiers in molecular dynamics simulations of DNA

It has been known for decades that DNA is extremely flexible and polymorphic, but our knowledge of its accessible conformational space remains limited. Structural data, primarily from X-ray diffraction studies, is sparse in comparison to the manifold configurations possible, and direct experimental examinations of DNA's flexibility still suffer from many limitations. In the face of these shortcomings, molecular dynamics (MD) is now an essential tool in the study of DNA. It affords detailed structural and dynamical insights, which explains its recent transition from a small number of highly specialized laboratories to a large variety of groups dealing with challenging biological problems. MD is now making an irreversible journey to the mainstream of research in biology, with the attendant opportunities and challenges. But given the speed with which MD studies of DNA have spread, the roots remain somewhat shallow: in many cases, there is a lack of deep knowledge about the foundations, strengths, and limits of the technique. In this Account, we discuss how MD has become the most important source of structural and flexibility data on DNA, focusing on advances since 2007 of atomistic MD in the description of DNA under near-physiological conditions and highlighting the possibilities and shortcomings of the technique. The evolution in the field over the past four years is a prelude to the ongoing revolution. The technique has gained in robustness and predictive power, which when coupled with the spectacular improvements in software and hardware has enabled the tackling of systems of increasing complexity. Simulation times of microseconds have now been achieved, with even longer times when specialized hardware is used. As a result, we have seen the first real-time simulation of large conformational transitions, including folding and unfolding of short DNA duplexes. Noteworthy advances have also been made in the study of DNA-ligand interactions, and we predict that a global thermodynamic and kinetic picture of the binding landscape of DNA will become available in a few years. MD will become a crucial tool in areas such as biomolecular engineering and synthetic biology. MD has also been shown to be an excellent source of parameters for mesoscopic models of DNA flexibility. Such models can be refined through atomistic MD simulations on small duplexes and then applied to the study of entire chromosomes. Recent evidence suggests that MD-derived elastic models can successfully predict the position of regulatory regions in DNA and can help advance our understanding of nucleosome positioning and chromatin plasticity. If these results are confirmed, MD simulations can become the ultimate tool to decipher a physical code that can contribute to gene regulation. We are entering the golden age of MD simulations of DNA. Undoubtedly, the expectations are high, but the challenges are also enormous. These include the need for more accurate potential energy functionals and for longer and more complex simulations in more realistic systems. The joint research effort of several groups will be crucial for adapting the technique to the requirements of the coming decade.