CDI-Type I Collaborative Research: Multi-Scale Modeling of Protein-Modulated DNA Large-Scale Dynamics by Free Energy Surface Matching

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Protein-DNA interactions govern essentially all major genetic transactions within the cell including, for example, DNA replication, repair, transcription and recombination. These actions, which begin locally at the nm-sized site of protein-DNA binding, often generate very large, ?Ým-scale DNA conformational changes. The enormously broad length and time scales invoked in these complex dynamical systems create formidable challenges for computational modeling. This project addresses this challenge by proposing a transformative, multi-scale computational method that captures the time-evolution of large protein-DNA complexes on biologically relevant length/time scales (e.g., micron/millisecond and longer). Our method begins with (one-time) massively parallel MD computations and umbrella sampling of the protein domain to establish an unperturbed free energy surface in the presence of a short (atomically-detailed) fragment of the DNA duplex. Next, we couple a rod model of the long DNA duplex to the protein (by geometric protein boundary conditions) and form a reduced-order dynamical system (Fokker-Planck probability) model of the entire protein-DNA complex for the dominant degrees of freedom. The resulting Fokker-Plank model captures the complete (two-way) dynamic coupling of the rod/DNA and protein domains and enables integration over the desired long length/time scales. We illustrate our method on two large and challenging systems; namely 1) the relaxation of DNA supercoils by human topoisomerase I, and 2) the packing and ejection of dsDNA from viral capsids in bacteriophages.This research aims at long standing challenges in predicting the dynamical behavior of large biomolecular systems on long length and time scales. These predictions are essential for understanding fundamental cellular processes (including DNA transcription, replication, and repair) and interpreting exciting results from single molecule experiments. More broadly, our method provides a systematic means to couple atomistic to continuum level (e.g. micron-scale) descriptions of matter in a wide range of fields. Other fields may include DNA/RNA complexes that form large scale nucleic acid (origami) structures for scaffolding, computing, or nanopropelling; carbon nanotubes interacting with organic and inorganic nanoparticles; nanowires and their use for bio-molecular detection; and the structural dynamics of flagella, collagen fibers and cellular cytoskeleton elements (e.g., actin, neurofilaments, microtubules), among others.