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: Studies of conformation-dependent chemical shifts and anisotropies. Earlier empirical treatments of shifts in proteins will be extended to the non-exchangeable protons in nucleic acids; ab initio quantum chemistry and empirical calculations will be used to explore patterns of shift anisotropies in peptide and nucleic acid fragments. Updated refinement methods. Refinement models will be developed that incorporate conformational disorder through the """"""""locally enhanced sampling"""""""" model that uses multiple copies of portions of the macromolecule. Studies on protein and nucleic acid dynamics. Models for calculating rates of both homonuclear and heteronuclear relaxation, with increased attention to anisotropic tumbling and to conformational disorder, will be studied, along with contributions from internal motions to chemical shift anisotropy (CSA) relaxation and to CSA-dipolar cross-correlated relaxation. Applications to important biological macromolecules. In collaborative experimental/theoretical efforts, these ideas will be applied to systems of significant interest to biochemistry, including: (a) studies of conformational heterogeneity and disorder in thioredoxin and zinc- finger/DNA complexes; (b) studies of the binding of duocarmycin analogues to DNA; (c) work on LFA1 integrin-ligand domains and on the interactions of zinc fingers with 5S RNA; (d) use of direct dipolar couplings and chemical shift analysis for structure elucidation in small RNA and RNA/protein interactions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
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
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
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

Showing the most recent 10 out of 28 publications