Brandeis Professor of Biochemistry, Dorothy Kern, recently published a research briefing in “Nature Magazine” concerning her latest work in protein dynamics. Kern details how a new technique involving nuclear magnetic resonance (NMR) may shed light onto the structure that proteins take on when they are at functional high energy states.
As described in the article, proteins have a “dynamic ‘personality’” since they continually morph between stable and unstable conformations, creating an overall “energy landscape” that characterize their tendency to be in one structure over the other at a given time.
Kern notes that when proteins are performing key biological activities, they are in highly unstable structures that are fleeting. However, current methods used in structural biology to uncover the specific three-dimensional structure of proteins better characterizes proteins under more stable conditions. The main challenge is that while proteins perform crucial functions in high energy states, current techniques are not able to fully capture the structure of these fleeting conformations.
To solve this issue, Kern and her team are developing a technique where the high energy structures of proteins can be deduced by their change in structure in response to binding with metal ions. NMRs produce a “chemical fingerprint” for different molecules by representing atoms in chemical environments with peaks on a graph. If the NMR of a protein after metal ions have been bound to it is compared with the NMR of proteins before during relaxation, scientists can deduce the structure of high energy molecules.
The team of researchers applied this technique to an enzyme protein called adenylate kinase, which plays an important role in reactions that generate the energy currency for cells to use in their regular metabolic processes. The researchers discovered that this technique was able to characterize the minute changes in the enzyme structure to a high accuracy. Combined with recent advances in the applications of artificial intelligence to protein folding dynamics such as the software Alphafold, this workflow can be applied to gain insight into the roles and mechanisms of other proteins of interest.
Kern describes the process of undertaking this research project in the article, writing, “It took relentless work by my research team to show that … the technique can determine structures of proteins that exist for fractions of a second at atomic resolution.”
Kern is a Professor of Biochemistry at Brandeis and a Howard Hughes Medical Investigator. Overall, her research involves the use of biophysical analytical techniques to uncover how proteins and enzymes function in biological systems. Motivated by the continuous process of evolution, Kern also seeks to characterize how proteins and key enzymes have evolved to carry out the processes observed in higher level organisms.
This research briefing is a summary from the original research paper that was published in Nature Magazine titled “Structure Determination of High-Energy States in a Dynamic Protein Ensemble.”
