Wednesday, April 19, 2023, 1:30 pm — Videoconference / Virtual Event (see link below)
Evolution of Energy Landscapes and its Exploitation for Drug and Enzyme Design
Dorothee Kern
HHMI/ Brandeis University, Dept. of Biochemistry, Waltham, USA
Why can we not design efficient enzymes or highly selective drugs to date? While one can solve high resolution structures of ground states experimentally, and even now predict them with Alphafold; for biological function proteins need to traverse the entire energy landscape from the lowest energy state over the transition states into higher energy states. Therefore, I will first share a novel approach to visualize the structures of transition-state ensembles (TSEs), that has been stymied due to their fleeting nature despite their crucial role in dictating the speed of biological processes. We determined the transition-state ensemble in the enzyme adenylate kinase by a synergistic approach between experimental high-pressure NMR relaxation during catalysis and molecular dynamics simulations (1). Second, a novel general method to determine high resolution structures of high-energy states that are often the biologically reactive species will be described (2). With the ultimate goal to apply this new knowledge about energy landscapes in enzyme catalysis for designing better biocatalysts, in "forward evolution" experiments, we discovered how directed evolution reshapes energy landscapes in enzymes to boost catalysis by nine orders of magnitude relative to the best computationally designed biocatalysts. The underlying molecular mechanisms for directed evolution, despite its success, had been illusive, and the general principles discovered here (dynamic properties) open the door for large improvements in rational enzyme design (3).
To gain insight into one of the most fundamental evolutionary events, the development of circadian rhythms, we find and characterize the most ancient, primitive biological clock (4). Finally, visions (and success) for putting protein dynamics at the heart of drug design are discussed.
1. J. B. Stiller et. al., Probing the Transition State in Enzyme Catalysis by High-Pressure NMR Dynamics 2019, Nature Catalysis (2019) 2, 726–734
2. J. B. Stiller et. al., Structure Determination of High-Energy States in a Dynamic Protein Ensemble Nature 2022, 603, 528–535
3. R. Otten et. al., How directed evolution reshapes energy landscapes in enzymes to boost catalysis Science 2020, 2020 Dec 18;370(6523):1442-1446.
4. W. Pitsawong et al., From primordial clocks to circadian oscillators Nature 2023, 616(7955):183-189
Hosted by: Vivian Stojanoff
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