Adriaan Bax, Ph.D.

NIH Distinguished Investigator

Biophysical Nuclear Magnetic Resonance Spectroscopy Section, Laboratory of Chemical Physics

NIDDK

Building 5, Room 126
5 Memorial Dr
Bethesda, MD 20814

+1 301 496 2848

adriaan.bax@nih.gov

Research Topics

The ultimate goal is to extend the capability of currently available nuclear magnetic resonance (NMR) methods to study the structure, dynamics, and folding of proteins, including those embedded in membranes, as well as static and dynamic interactions between macromolecules.

Current Research

Our research is focused on developing new NMR techniques and approaches for determining the structure and dynamics of bioactive molecules. Our research focuses on four separate areas.

Our first area of interest is in improving the accuracy of biomolecular structures determined by NMR data. We are especially interested in developing the following: (a) better measurement techniques for interproton distances and dihedral angles from nuclear Overhauser effects (NOE) and J couplings, and (b) further development of quantitative relations between molecular structure and chemical shifts as well as chemical shift anisotropy.

Our second area of interest is in characterizing long-range intramolecular order by the measurement of dipolar couplings and rotational diffusion anisotropy. The methods we are developing address the main shortcoming of conventional NMR methods—the fact that they provide strictly local structural constraints.  These methods will be particularly useful for studying molecular machines with partially flexible hinges, such as found in molecular motors, and allosterically controlled enzymes.

Our third area of interest is in using fast switching of hydrodynamic pressure to modulate the folding-unfolding equilibrium of proteins and to collect real-time data on the complex process by which proteins can switch their structure.  This research is of interest to both enhancing our understanding of the all important protein folding process, but also for gaining experimental insights in misfolding, a process that underlies amyloid diseases.

Our fourth area of interest is in developing NMR technology that facilitates the structure determination process and makes it applicable to larger molecular weight systems. Effectively, our aim is to integrate de novo modeling approaches with sparse or easily accessible experimental data, including chemical shifts and amide and methyl group NOE data.

Applying our Research

Deeper understanding of macromolecular structures and their dynamic properties will improve our knowledge of how biology works at the molecular level and provide insights into complex diseases, including amyloidosis (such as Alzheimer’s, diabetes, and Parkinson’s), cancer, and many others. This will providing opportunities to intervene in such disease processes in a targeted manner.

Need for Further Study

Further technological improvements are needed at all levels, ranging from very fundamental issues such as the relation between chemical shift and local structure, enhanced methods to extract chemical shift and other structural restraints from complex NMR spectra, to the development of computationally sophisticated procedures at the interface between molecular modeling and classical experimental structure determination. Together, this will expedite the process and extend its applicability to ever larger and more complex systems.

Biography

  • Ph.D., Delft University of Technology, 1981
  • B.S., Delft University of Technology, 1978

Selected Publications

  1. Lorieau JL, Louis JM, Schwieters CD, Bax A. pH-triggered, activated-state conformations of the influenza hemagglutinin fusion peptide revealed by NMR. Proc Natl Acad Sci U S A. 2012;109(49):19994-9.

  2. Charlier C, Alderson TR, Courtney JM, Ying J, Anfinrud P, Bax A. Study of protein folding under native conditions by rapidly switching the hydrostatic pressure inside an NMR sample cell. Proc Natl Acad Sci U S A. 2018;115(18):E4169-E4178.

  3. Bax A. Weak alignment offers new NMR opportunities to study protein structure and dynamics. Protein Sci. 2003;12(1):1-16.

  4. Alderson TR, Charlier C, Torchia DA, Anfinrud P, Bax A. Monitoring Hydrogen Exchange During Protein Folding by Fast Pressure Jump NMR Spectroscopy. J Am Chem Soc. 2017;139(32):11036-11039.

  5. Chiliveri SC, Louis JM, Ghirlando R, Baber JL, Bax A. Tilted, Uninterrupted, Monomeric HIV-1 gp41 Transmembrane Helix from Residual Dipolar Couplings. J Am Chem Soc. 2018;140(1):34-37.


This page was last updated on April 11th, 2019