The primary objectives of this project are the characterization of conformation and energetics of nonnative states of proteins, the exploration of pH and salt induced unfolding and the development of models that permit maximum structural information to be extracted from NMR experiments on unfolded states of proteins. The primary computational tools utilized for these studies will be continuum solvation methods and molecular dynamics. These objectives will be approached by addressing three major specific aims. 1. Energetic models for the unfolding profiles of analysis of unfolded states will be developed and tested through studies on single domain polypeptide fragments from Protein A and Protein G. Utilizing experimental NMR data on these systems together with existing simulation results for the folding free energy profiles, continuum models for protein folding/unfolding will be developed and assessed. Of particular interest will be the use of continuum models to provide insight into the energetics of unfolded states and their associated statistical weights. 2. Models for acid unfolded states apomyoglobin will be developed in collaboration with Dyson and Wright, using NMR. Utilizing continuum methods to assess conformation dependent pH changes and molecular dynamics approaches to expose structure and fluctuations under low pH conditions, the investigators will characterize the nature of the low pH nonnative states of apomyoglobin. They will also examine the backbone and sidechain coupling constants in the nonnative states by extensive comparison with simpler dipeptide models and NMR data from Dyson and Wright. 3. The influence of salt on the nonnative states of the all beta protein, plastocyanin, will be examined using continuum solvation methods and explicit molecular dynamics. The investigation will explore the changes in thermodynamic stability of apoplastacyanin as a result of changes in ionic strength using continuum models. From explicit MD studies, they will also explore changes in structure and dynamics as a result of these changes in salt concentration. The detailed models to be developed will be compared directly to the NMR results on these systems and will help the interpretation planning of collaborative efforts ongoing with the Dyson and Wright laboratories.
| Bharatham, Nagakumar; Finch, Kristin E; Min, Jaeki et al. (2017) Performance of a docking/molecular dynamics protocol for virtual screening of nutlin-class inhibitors of Mdmx. J Mol Graph Model 74:54-60 |
| Laricheva, Elena N; Goh, Garrett B; Dickson, Alex et al. (2015) pH-dependent transient conformational states control optical properties in cyan fluorescent protein. J Am Chem Soc 137:2892-900 |
| Zeng, Xiancheng; Mukhopadhyay, Suchetana; Brooks 3rd, Charles L (2015) Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion. Proc Natl Acad Sci U S A 112:2034-9 |
| Goh, Garrett B; Hulbert, Benjamin S; Zhou, Huiqing et al. (2014) Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism. Proteins 82:1319-31 |
| Goh, Garrett B; Laricheva, Elena N; Brooks 3rd, Charles L (2014) Uncovering pH-dependent transient states of proteins with buried ionizable residues. J Am Chem Soc 136:8496-9 |
| May, Eric R; Arora, Karunesh; Brooks 3rd, Charles L (2014) pH-induced stability switching of the bacteriophage HK97 maturation pathway. J Am Chem Soc 136:3097-107 |
| Giamba?u, George M; Luchko, Tyler; Herschlag, Daniel et al. (2014) Ion counting from explicit-solvent simulations and 3D-RISM. Biophys J 106:883-94 |
| Bharatham, Nagakumar; Bharatham, Kavitha; Shelat, Anang A et al. (2014) Ligand binding mode prediction by docking: mdm2/mdmx inhibitors as a case study. J Chem Inf Model 54:648-59 |
| Joung, In Suk; Luchko, Tyler; Case, David A (2013) Simple electrolyte solutions: comparison of DRISM and molecular dynamics results for alkali halide solutions. J Chem Phys 138:044103 |
| Goh, Garrett B; Knight, Jennifer L; Brooks 3rd, Charles L (2013) pH-dependent dynamics of complex RNA macromolecules. J Chem Theory Comput 9:935-943 |
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