Novel coarse-graining and multiscale simulation methods are developed and applied in mechanistic studies of supramolecular protein-nucleic acid assemblies. The coarse-grained model relies on an intermediate- resolution model that preserves quasi-atomistic resolution and gains transferability from a physically- motivated all-atom force field like interaction potential. A multiscale modeling scheme is proposed where a biomolecular system is represented with a mixed coarse-grained/all-atom representation. Applications focus on DNA mismatch recognition and initiation of repair by bacterial MutS and eukaryotic MSH2-MSH6 as well as transcription by yeast RNA polymerase II. Both systems involve complex dynamic interactions of multi- subunit protein complexes with nucleic acids that will be addressed with a combination of unbiased and biased simulations at both the all-atom and coarse-grained levels. Biophysical insight will consist of specific mechanistic and energetic aspects of the mismatch recognition process in MutS/MSH2-MSH6 and the elongation phase in RNA polymerase II but also provide a more general understanding of translocation of proteins along nucleic acids which plays a crucial role in many protein-nucleic acid interactions. Computational studies of RNA polymerase II will be validated through experimental characterization of RNA polymerase II mutants with predicted altered functional properties. 1
Computer simulations based on novel methodology are used to study the structure and dynamics of protein- nucleic acid complexes. Molecular complexes involved in repair of damaged DNA and in the transcription from DNA to RNA are studied to gain detailed mechanistic insight into fundamental biology and processes related to disease, in particular cancer. Experiments are carried out to validate computational predictions for the transcription process. 1
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