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

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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

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Brazhnik, Paul
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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Wang, Beibei; Sexton, Rachel E; Feig, Michael (2017) Kinetics of nucleotide entry into RNA polymerase active site provides mechanism for efficiency and fidelity. Biochim Biophys Acta 1860:482-490
Kar, Parimal; Feig, Michael (2017) Hybrid All-Atom/Coarse-Grained Simulations of Proteins by Direct Coupling of CHARMM and PRIMO Force Fields. J Chem Theory Comput 13:5753-5765
Wang, Beibei; Francis, Joshua; Sharma, Monika et al. (2016) Long-Range Signaling in MutS and MSH Homologs via Switching of Dynamic Communication Pathways. PLoS Comput Biol 12:e1005159
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Chodavarapu, Sundari; Jones, A Daniel; Feig, Michael et al. (2016) DnaC traps DnaB as an open ring and remodels the domain that binds primase. Nucleic Acids Res 44:210-20
Yu, Isseki; Mori, Takaharu; Ando, Tadashi et al. (2016) Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm. Elife 5:
Feig, Michael; Harada, Ryuhei; Mori, Takaharu et al. (2015) Complete atomistic model of a bacterial cytoplasm for integrating physics, biochemistry, and systems biology. J Mol Graph Model 58:1-9
Wang, Beibei; Opron, Kristopher; Burton, Zachary F et al. (2015) Five checkpoints maintaining the fidelity of transcription by RNA polymerases in structural and energetic details. Nucleic Acids Res 43:1133-46
Kar, Parimal; Gopal, Srinivasa Murthy; Cheng, Yi-Ming et al. (2014) Transferring the PRIMO Coarse-Grained Force Field to the Membrane Environment: Simulations of Membrane Proteins and Helix-Helix Association. J Chem Theory Comput 10:3459-3472

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