Bruker Corporation and Lawrence Berkeley National Laboratory (Berkeley Lab) today announced a collaboration to develop and distribute new structural biology methods and tools to integrate Small-Angle X-ray Scattering (SAXS) with Nuclear Magnetic Resonance (NMR). The goal of this collaboration is to develop a set of integrated SAXS and NMR data analysis algorithms for determining the structures of larger multi-domain proteins and protein complexes with DNA, RNA or other proteins. Such multi-modality approaches based on complementary analytical technologies play a key role in helping researchers answer increasingly complex questions in structural biology and drug development, and hold the potential for advancements in clinical research applications.
Traditional NMR three-dimensional (3D) atomic structure determination of the individual protein domains will be combined and integrated with the determination of overall size, shape and envelope constraints provided by SAXS. This approach will yield more accurate structures of larger multi-domain proteins and complexes under near-native solution conditions than what can be solved currently by NMR alone. Importantly, the integrated NMR and SAXS approach has been shown to help in the elucidation of important functional information about intrinsically flexible, unstructured, or partially unfolded domains.
“Hybrid methods are going to be essential for solving structures of larger biomolecules and biomolecular complexes,” stated Dr. John Markley, Steenbock Professor of Biomolecular Structure, and Head of the National Magnetic Resonance Facility at Madison (NMRFAM) at the University of Wisconsin-Madison.
Protein structure determination is crucial for a broad range of applications from fundamental biological research to next-generation drug development. High magnetic field NMR is unique in its capability to study the detailed structure and dynamics of proteins in solution, the native environment of many proteins. This allows NMR to elucidate the structures of proteins with flexible domains or multiple configurations, features that are often not directly accessible with static techniques such as crystallography or electron microscopy. However, typical NMR structures are not as accurate as the best protein structures from X-ray crystallography, and currently the use of NMR for protein structure determination in solution has its upper size limits typically near 50–70 kDa proteins.
Approaching this limit already requires the use of all modern NMR techniques, such as ultra-high field 800-1000 MHz magnets, isotopic labeling schemes, advanced pulse sequences and NMR electronics, and highest sensitivity CryoProbes™. Even with all these capabilities, solution NMR often lacks the ability to determine the exact global structure of larger molecular assemblies or multi-domain proteins. NMR has significant advantages in that it can study proteins in solution near native physiological conditions, can obtain dynamic information for different regions and domains of a protein, and allow access to functionally very important information on protein flexibility, intrinsically unstructured regions, partial protein folding, and in some cases multiple accessible protein conformations.