Using a collection of modern 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 provide well resolved spectra, structures and detailed characterization of dynamic properties. NMR studies clarified the relationship of enzymatic function to protein conformational exchange, including active site loop motions and substrate repositioning in a number of examples.
Ann McDermott’s research group studies the structure, flexibility, and function of proteins using magnetic resonance methods. For example, we study the structure and function of potassium ion channels, which play crucial roles in diverse contexts, from bacteria to the human nervous system. Our work illuminated the role of an ion-depleted state and provided evidence for strong allosteric coupling in channel regulation, using the prototypical prokaryotic ion channel KcsA. As for many enzymes and drug targets, ligand binding is associated with internal motions. The characteristic timescales of active-site flexible loop motions in other proteins have been studied in the past by the McDermott group, and ongoing studies of the channel position us to carry out detailed dynamics of the channel.
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 investigations in the McDermott group are specifically labeling proteins with radicals in order to use them both as polarizing agents and structural probes
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