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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
Zip Code
Janowski, Pawel A; Cerutti, David S; Holton, James et al. (2013) Peptide crystal simulations reveal hidden dynamics. J Am Chem Soc 135:7938-48
Case, David A (2013) Chemical shifts in biomolecules. Curr Opin Struct Biol 23:172-6
Xia, Junchao; Case, David A (2012) Sucrose in aqueous solution revisited, Part 1: molecular dynamics simulations and direct and indirect dipolar coupling analysis. Biopolymers 97:276-88
Xia, Junchao; Case, David A (2012) Sucrose in aqueous solution revisited, Part 2: adaptively biased molecular dynamics simulations and computational analysis of NMR relaxation. Biopolymers 97:289-302
Xia, Junchao; Margulis, Claudio J; Case, David A (2011) Searching and optimizing structure ensembles for complex flexible sugars. J Am Chem Soc 133:15252-5
Tang, Sishi; Case, David A (2011) Calculation of chemical shift anisotropy in proteins. J Biomol NMR 51:303-12
Tolbert, Blanton S; Miyazaki, Yasuyuki; Barton, Shawn et al. (2010) Major groove width variations in RNA structures determined by NMR and impact of 13C residual chemical shift anisotropy and 1H-13C residual dipolar coupling on refinement. J Biomol NMR 47:205-19
Wong, Vance; Case, David A; Szabo, Attila (2009) Influence of the coupling of interdomain and overall motions on NMR relaxation. Proc Natl Acad Sci U S A 106:11016-21
Fuller, Amelia A; Du, Deguo; Liu, Feng et al. (2009) Evaluating beta-turn mimics as beta-sheet folding nucleators. Proc Natl Acad Sci U S A 106:11067-72
Wong, Vance; Case, David A (2008) Evaluating rotational diffusion from protein MD simulations. J Phys Chem B 112:6013-24

Showing the most recent 10 out of 17 publications