Adriaan Bax, Ph.D., NIH Distinguished Investigator

Research Goal

Our laboratory develops and applies nuclear magnetic resonance (NMR) methods to obtain more complete and quantitative descriptions of biomolecular structure and dynamics. We focus on processes that are difficult to capture by conventional structural methods, including protein folding and misfolding, transient conformational states, and dynamic interactions between macromolecules.

Current Research

Our work combines NMR methodology development with applications to proteins and other biological samples. Current efforts emphasize three areas:

Quantitative structure and dynamics. We improve measurements of interatomic distances, dihedral angles, chemical shifts, residual dipolar couplings, and molecular dynamics, and develop computational approaches that translate these data into more accurate descriptions of protein structure and motion. These measurements also provide stringent experimental tests of structural models derived from other experimental and computational approaches.

Time-resolved protein folding and misfolding. Rapid pressure changes inside an NMR sample cell shift protein folding equilibria and allow us to follow short-lived conformations as proteins fold, unfold, or oligomerize. Pressure-jump NMR provides residue-specific kinetic and structural information and has recently enabled structural characterization of a transient protein-folding intermediate.

New analytical applications. We are developing noninvasive methods to collect microscopic particles generated deep in the lung during breathing and to quantify their chemical composition using NMR and mass spectrometry. This approach is designed to provide chemically specific information about peripheral airway-lining fluid without invasive sampling.

We also develop pulse sequences, software, and web-based analysis tools and make these resources broadly available to the research community.

Applying our Research

NMR is particularly well suited to studying biomolecules in solution and to detecting states that are transient, weakly populated, or structurally heterogeneous. By increasing the accuracy, speed, and range of NMR measurements, our work aims to reveal mechanisms of protein folding, misfolding, oligomerization, and molecular recognition at atomic detail. These insights are relevant to diseases associated with aberrant protein assembly, while the underlying methods are broadly applicable across structural biology. Our respiratory work explores a complementary application: noninvasive access to the chemistry of peripheral airway-lining fluid for studies of lung physiology and disease.

Need for Further Study

Important challenges remain in obtaining reliable structural information from fleeting or heterogeneous biomolecular states and in combining experimental restraints with increasingly powerful computational structure models. Further gains in NMR sensitivity, time resolution, and quantitative interpretation should make it possible to characterize more complex systems and rarer states. For respiratory sampling, larger studies will be needed to establish biological variability and determine which chemical signatures are most informative for studies of lung physiology and disease.

Research in Plain Language

Proteins are not rigid objects. They constantly move, interact, fold, and sometimes misfold. Some of the most important structures exist only briefly, making them difficult to see with conventional methods. Our lab develops NMR techniques that can detect these short-lived states and show, atom by atom, how molecules change over time.

One approach rapidly changes pressure inside an NMR sample to start protein folding or unfolding, allowing us to follow otherwise hidden intermediate structures. We also develop experimental methods and software that make NMR measurements more accurate and easier to interpret.

In a separate effort, we collect microscopic particles produced deep in the lung during breathing and analyze their chemical contents. This may provide a noninvasive way to study the fluid that lines the small airways.