Using the most recent nuclear magnetic resonance methods, the McDermott lab studies the structure, function, and conformational dynamics of proteins in native-like environments. Efforts of the research group demonstrated that NMR spectra of “solid state” proteins, such as membrane proteins in native lipid bilayers, or protein assemblies like viral coats, can serve as the basis for structural and dynamic investigations. NMR studies clarified the accordance of enzymatic function to protein conformational exchange, including active site loop motions and substrate repositioning.

Membrane proteins are important players in many physiological processes such as transmembrane signaling, energy transduction, and ion transport and comprise ~30% of the genes encoded in eukaryotic genomes. Solid-state NMR offers the unique opportunity to study membrane proteins at atomic resolution while they are in a native-like lipid bilayer. We study the structure and dynamics of several such systems. These include KcsA, a bacterial potassium channel, E.Coli Subunit c, which is part of the ATP synthase machinery, and the photosynthetic light harvesting protein LH1.


Membrane Proteins

Dynamic nuclear polarization (DNP) is a technique for transferring polarization from unpaired electrons to nearby nuclei to enhance the signal-to-noise ratio of the NMR spectra. We develop novel methods to apply DNP to membrane proteins and viruses. In addition to using DNP to enable studies of complex systems such as KcsA and the Pf1 bacteriophage, ongoing studies in the McDermott group are specifically labeling proteins with radicals in order to use them both as polarizing agents and structural probes.


We are primarily interested in the protein-DNA interactions which hold the massive 36 MDa virion together. Understanding these interactions in detail would likely yield a model of virus structure and assembly that can be applicable to a broad range of filamentous bacteriophages. To this end, and to overcome the challenges of working with such a large system, we have employed novel techniques such as DNP and innovative chemical labeling schemes. We are also investigating the role of hydration in Pf1 structure and dynamics. Water is thought to be an important structural element, mediating the interactions between the DNA and capsid (coat protein) and allowing the DNA some degree of mobility. We are interested in whether sub-populations of water (i.e. bulk vs. interfacial water) exist within the virion, and, if so, what their dynamics tell us about viral function

Filamentous Phage Pf1

For most enzymes and drug targets, ligand binding is associated with the motion of a flexible loop or domain and conformational changes. We investigate the characteristic timescales of an active-site loop motion in the protein TIM. Similarly, metal-substrate geometry and conformational exchange rates are studied for metalloenzymes, such as the drug target cytochrome P450. An advantage of solid-state NMR is the presence of anisotropic interactions such as dipolar, quadrupolar, and chemical shift anisotropy (CSA), which are an abundant source of information for proteins dynamics. Currently, we investigate slow conformational change (millisecond-to-second timescale) by refocusing dipolar interactions through a very high-efficiency 1D dynamics detection scheme (CODEX), described by Schmidt-Rohr. We also study intermediate timescale (millisecond-to-microsecond) through T1ρ measurements monitoring the motion of CSA tensors. The quantitative application of these techniques to proteins and the design of original new pulse sequences are two main directions of our research.

Protein Dynamics

Cytochromes P450 are heme monooxygenases that play critical roles in the biosynthesis of lipids, steroids, antibiotics, and drug metabolism. Understanding the active site structure and dynamics is important for drug discovery and providing insight on biological processes. Cryogenic crystal structures of numerous P450 isoforms show the substrate positioned too far away from the heme to be the catalytically relevant binding mode. Molecular dynamics simulations have shown that at room temperature the ligand is position correctly for chemistry. We use solid state NMR to collect structural information of N-palmitoylglycine (NPG) bound to cytochrome P450 BMP in order to confirm the low temperature binding mode and prove the room temperature conformation.

Cytochrome P450

In collaboration with the group of Professor Hao Wu, we are studying the complex of RIP1/RIP3, known to induce necroptosis, an alternative cell death mechanism. Our solid-state NMR experiments support the formation of an amyloid fibril by RIP1 and RIP3 and allow the identification of the amyloid core near the unique homlogous sequence RHIM (RIP homotypic interaction motif). This study provides insight into the RIP kinases’ structural changes regulating the cell’s death and expands the realm of amyloids to complex formation and signaling.

Functional Prions