The principal goals of this project are the development of algorithms that allow one to make the best use of NMR data to determine solution structures of biomolecules, to assess in a systematic fashion their accuracy and precision, and to explore the extent to which dynamical information can be extracted from NMR data. This will involve the following components: New models for chemical shifts in biomolecules. We will develop automated quantum chemical/molecular mechanical (QM/MM) models to compute chemical shifts and anisotropies in proteins, carbohydrates, and nucleic acids. Results will be used to examine conformation flexibility in ubiquitin, helix junctions in DN and RNA, and conformational flexibility in collagen peptides. Studies on protein and nucleic acid dynamics. Long-time scale molecular dynamics simulations will be used to model NMR relaxation, with attention paid to anisotropic tumbling, to the correlation between internal and overall motions, and to conformational disorder. Analytical models with adjustable parameters will be constructed to allow direct fits to experimental data. This will include an analysis of contributions from both overall and internal motions to chemical shift anisotropy (CSA) relaxation and to CSA-dipolar cross-correlated relaxation. Principal applications will be to elongated molecules such as duplex DNA and collagen, and to proteins with a folded core domain and a disordered tail region.
Nuclear magnetic resonance (NMR) spectroscopy provides a powerful tool for probing the properties of proteins and nucleic acids under conditions like those in living cells. The project uses computational tools to help gain the most information from NMR, promoting our understanding of basic biochemical processes that underlie both healthy and diseased cells. Applications of biomedical interest include studies of collagen peptides related to connective tissue disease, and studies of RNA structure in HIV and other viruses.
|Hoop, Cody L; Zhu, Jie; Nunes, Ana Monica et al. (2017) Revealing Accessibility of Cryptic Protein Binding Sites within the Functional Collagen Fibril. Biomolecules 7:|
|Shirts, Michael R; Klein, Christoph; Swails, Jason M et al. (2017) Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset. J Comput Aided Mol Des 31:147-161|
|Debiec, Karl T; Cerutti, David S; Baker, Lewis R et al. (2016) Further along the Road Less Traveled: AMBER ff15ipq, an Original Protein Force Field Built on a Self-Consistent Physical Model. J Chem Theory Comput 12:3926-47|
|Hsu, Che-Hsiung; Park, Sangho; Mortenson, David E et al. (2016) The Dependence of Carbohydrate-Aromatic Interaction Strengths on the Structure of the Carbohydrate. J Am Chem Soc 138:7636-48|
|Gutmanas, Aleksandras; Adams, Paul D; Bardiaux, Benjamin et al. (2015) NMR Exchange Format: a unified and open standard for representation of NMR restraint data. Nat Struct Mol Biol 22:433-4|
|Swails, Jason; Zhu, Tong; He, Xiao et al. (2015) AFNMR: automated fragmentation quantum mechanical calculation of NMR chemical shifts for biomolecules. J Biomol NMR 63:125-39|
|Giamba?u, George M; York, Darrin M; Case, David A (2015) Structural fidelity and NMR relaxation analysis in a prototype RNA hairpin. RNA 21:963-74|
|Salmon, Loïc; Giamba?u, George M; Nikolova, Evgenia N et al. (2015) Modulating RNA Alignment Using Directional Dynamic Kinks: Application in Determining an Atomic-Resolution Ensemble for a Hairpin using NMR Residual Dipolar Couplings. J Am Chem Soc 137:12954-65|
|Fu, Iwen; Case, David A; Baum, Jean (2015) Dynamic Water-Mediated Hydrogen Bonding in a Collagen Model Peptide. Biochemistry 54:6029-37|
|Giamba?u, George M; Gebala, Magdalena K; Panteva, Maria T et al. (2015) Competitive interaction of monovalent cations with DNA from 3D-RISM. Nucleic Acids Res 43:8405-15|
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