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Biochemistry Seminar

Thursday, April 13, 2023
4:00pm to 5:00pm
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Gates Annex B122
Evolution of Energy Landscapes and its Exploitation for Drug and Enzyme Design
Dorothee Kern, Professor of Biochemistry, Department of Biochemistry, HHMI/Brandeis University,

The essential role of protein dynamics for enzyme catalysis has become more generally accepted. Since evolution is driven by organismal fitness hence the function of proteins, we are asking the question of how enzymatic efficiency has evolved.

First, I will address the evolution of enzyme catalysis in response to one of the most fundamental evolutionary drivers, temperature. Using Ancestral Sequence Reconstruction (ASR), we answer the question of how enzymes coped with an inherent drop in catalytic speed caused as the earth cooled down over 3.5 billion years. Tracing the evolution of enzyme activity and stability from the hot-start towards modern hyperthermophilic, mesophilic and psychrophilic organisms illustrates active pressure versus passive drift in evolution on a molecular level (1).

Second, I will 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 (2).

Third, a novel general method to determine high resolution structures of high-energy states that are often the biologically reactive species will be described (3). 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 (4). Finally, visions (and success) for putting protein dynamics at the heart of drug design are discussed.

  1. V. Nguyen et. al., Evolutionary Drivers of Thermoadaptation in Enzyme Catalysis" Science 2017, 355(6322):289-294
  2. J. B. Stiller et. al., Probing the Transition State in Enzyme Catalysis by High-Pressure NMR Dynamics 2019, Nature Catalysis (2019) 2, 726–734
  3. J. B. Stiller et. al., Structure Determination of High-Energy States in a Dynamic Protein Ensemble Nature 2022, 603, 528–535
  4. R. Otten et. al., How directed evolution reshapes energy landscapes in enzymes to boost catalysis Science 2020, 2020 Dec 18;370(6523):1442-1446.

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For more information, please contact Ann Mao by phone at (626) 395-6524 or by email at [email protected].