Movement is key: The role of protein dynamics in enzyme catalysis

Woman with long dark hair in a blue lab coat and glasses.
Dr. Shuaihua Gao.

In Stanley Hall at UC Berkeley, at the end of a tidy bench in a black rubber bucket of ice are two tubes of designed DNA. At a terminal next to the bench sits Dr. Shuaihua Gao. She compares multiple DNA sequences by aligning them on the computer screen and confirming the DNA meets her designs. Insights from these experiments could change the way we view enzyme catalysis and help develop lifesaving medicines.

Gao works in the Klinman Lab, where researchers are taking a second look at how enzymes catalyze reactions. Understanding enzyme catalysis helps us develop safe, novel medicines and efficient, clean industrial processes. Their experiments reveal how central “protein dynamics,” or the movement of the enzyme, is across many different enzyme reactions. This deeper understanding of protein dynamics will play an important role as we engineer new enzymes which can catalyze reactions never seen before in nature.

The conventional model of enzymes describes them as a “lock and key” with a rigid enzyme as the lock and the reacted molecule as the key.

With our increased biophysical understanding, the model has changed. Enzymes are now visualized floating in a solvent, their flexible structure guiding molecules to an interior site where charged molecules exert forces on each other, a process known as electrostatics. Gao and her colleagues are looking beyond electrostatics to understand how energy, in the form of heat, travels from the enzyme’s surface to its interior.

“Everybody is talking about the role of electrostatics but what about protein dynamics?” -Dr. Shuaihua Gao, researcher in The Klinman Lab Research Group

Gao’s research history began with applied protein engineering but she felt constrained by her lack of understanding of the fundamental mechanism of catalysis. During our interview, she grins while recalling her first interaction with the Klinman Lab. A long, spirited discussion of protein catalysis mechanisms lasting several hours would be exhausting for most of us, but Gao was inspired and convinced that this was the place for her to explore the fundamental science of how enzymes work alongside “these brilliant colleagues.”

Enzymes are macromolecules, mostly proteins. They are produced by living cells as their size and complexity make it impossible to synthesize even a small enzyme in a chemistry lab. A common enzyme macromolecule might have a mass that’s over 2500 times that of a water molecule. Composed of a chain of amino acids strung together like beads with different chemical properties, they self-fold into complex three dimensional shapes similar to headphone cords in a pocket. Though each enzyme structure is unique based on its sequence of amino acids, they are far from static. Instead, they have a motion reminiscent of breathing. Protein dynamics is the study of this motion.

Gao and her colleagues are looking into the role that protein dynamics play in enzyme reactions. Their observations show that protein dynamics are central to efficient catalysis across three of the seven enzyme groups. This information can help engineers develop new therapeutic and sustainable commercial uses for enzymes. A folded enzyme speeds up the reactions of neighboring “small” molecules or reactants, a process known as catalysis. A common enzyme can speed up a chemical reaction 10,000,000,000,000,000,000,000,000 times over its natural rate.

Enzymes’ ability to catalyze reactions without being consumed in the process makes them essential for all of life. Engineered for high-specificity, efficiency and safety, they are used to treat a variety of enzyme deficiencies and cancers. Ninety percent of the more than 200 enzyme products currently on the market are therapeutics.

But enzymes’ commercial potential extends beyond just therapeutics. With modern protein engineering techniques, enzymes are catalyzing industrial chemical reactions that never occurred in nature. Enzymes are produced by living cells and are biodegradable for easy disposal, making them a sustainable alternative to industrial chemical processes. The nature of catalysis is to perform reactions efficiently. This helps us reach our green chemistry goals of conserving water and energy. Enzymes have historically played a key role in many fermentation industries including brewing, baking, cheesemaking and tanning. With modern protein engineering, enzymes are increasingly taking on industrial, chemical and manufacturing processes. The average consumer is probably using enzymes directly in toothpastes, hair and skin care products, and detergents.

“Enzymes speed up reactions. We want enzymes to perform novel reactions and fast. To do that we are looking at how heat gets into the enzyme to help the reaction.” -Dr. Emily Thompson, researcher in the Klinman Lab Research Group.

The Klinman lab examines the contribution of protein dynamics on enzyme catalysis. Protein dynamics looks at the mobility of the enzyme. Using three dimensional mapping that shows the enzyme’s shape, along with knowledge of the genetic code and its corresponding sequence of amino acids, the protein can be tweaked to explore the effects of small structural changes. These small structural changes and their newly predictable effects will become tools for protein engineers to use when developing novel enzymes.

What are some examples of protein dynamics? Amino acids are strung together to form a protein. Enzymes have evolved to optimize their position or “packing” in three dimensional space. Some amino acids are larger and provide leverage for the enzyme to use when catalyzing the reaction. Exchanging them for smaller residues creates “packing defects” based on their sizes and the way they occupy space relative to their neighbors. Understanding these packing defects and their effect on catalytic efficiency is important when designing new enzymes or modifying existing enzymes.

Another interesting aspect of protein dynamics is “thermodynamic networks.” Some reactions require heat. Thermodynamic networks are pathways of tightly bound atoms that efficiently transfer heat, as vibrational energy, from the surface to the interior where it helps speed up the reaction. Changing just a few of these residues can have a large effect on the enzyme’s rate of reaction. Understanding how energy, in the form of heat, travels into the enzyme’s interior is crucial to understanding catalysis.

Gao swivels in her chair to talk with her lab mate, Dr. Paolo Zaragoza. They banter back and forth, contributing insights from their respective specialties of protein engineering and inorganic chemistry and making small, inside jokes. After a moment she swings back to edit her article with the new information from the encounter.

Dr. Gao’s article, “Hydrogen Deuterium Exchange within Adenosine Deaminase, a TIM Barrel Hydrolase, Identifies Networks for Thermal Activation of Catalysis,” will be submitted for publication in a peer-reviewed journal early next year as part of a series of articles by the Klinman Lab. This series of articles aims to show the important role played by protein dynamics across three of the seven categories of enzymes as a universal aspect of enzyme catalysis. With this project, Gao’s curiosity about fundamental mechanisms of catalysis as a protein engineer will provide future protein engineers with a deeper perspective as they design enzymes to improve our world and our health.

The work that engineers do shapes the world around us. But given the technical nature of that work, non-engineers may not always realize the impact and reach of engineering research. In E185: The Art of STEM Communication, students learn about and practice written and verbal communication skills that can bring the world of engineering to a broader audience. They spend the semester researching projects within the College of Engineering, interviewing professors and graduate students, and ultimately writing about and presenting that work for a general audience. This piece is one of the outcomes of the Fall 2019 E185 course.

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Master of Engineering at UC Berkeley with a focus on leadership. Learn more about the program through our publication.

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Berkeley Master of Engineering

Berkeley Master of Engineering

Master of Engineering at UC Berkeley with a focus on leadership. Learn more about the program through our publication.

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