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

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092949-03
Application #
8327188
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Brazhnik, Paul
Project Start
2010-09-24
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$284,446
Indirect Cost
$91,396
Name
Michigan State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Sharma, Monika; Predeus, Alexander V; Kovacs, Nicholas et al. (2014) Differential mismatch recognition specificities of eukaryotic MutS homologs, MutS? and MutS?. Biophys J 106:2483-92
Yildirim, Asli; Sharma, Monika; Varner, Bradley Michael et al. (2014) Conformational preferences of DNA in reduced dielectric environments. J Phys Chem B 118:10874-81
Wang, Beibei; Feig, Michael; Cukier, Robert I et al. (2013) Computational simulation strategies for analysis of multisubunit RNA polymerases. Chem Rev 113:8546-66
Sharma, Monika; Predeus, Alexander V; Mukherjee, Shayantani et al. (2013) DNA bending propensity in the presence of base mismatches: implications for DNA repair. J Phys Chem B 117:6194-205
Kar, Parimal; Gopal, Srinivasa Murthy; Cheng, Yi-Ming et al. (2013) PRIMO: A Transferable Coarse-grained Force Field for Proteins. J Chem Theory Comput 9:3769-3788
Wang, Beibei; Predeus, Alexander V; Burton, Zachary F et al. (2013) Energetic and structural details of the trigger-loop closing transition in RNA polymerase II. Biophys J 105:767-75
Feig, Michael; Sugita, Yuji (2013) Reaching new levels of realism in modeling biological macromolecules in cellular environments. J Mol Graph Model 45:144-56
Nedialkov, Yuri A; Burton, Zachary F (2013) Translocation and fidelity of Escherichia coli RNA polymerase. Transcription 4:136-43
Nedialkov, Yuri A; Opron, Kristopher; Assaf, Fadi et al. (2013) The RNA polymerase bridge helix YFI motif in catalysis, fidelity and translocation. Biochim Biophys Acta 1829:187-98
Harada, Ryuhei; Tochio, Naoya; Kigawa, Takanori et al. (2013) Reduced native state stability in crowded cellular environment due to protein-protein interactions. J Am Chem Soc 135:3696-701

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