High Flux Isotope Reactor a fit for Nobel laureate’s designer proteins

Nobel laureate and biochemist David Baker came to Oak Ridge National Laboratory in 2019 to use the IMAGINE instrument at the High Flux Isotope Reactor to see hydrogen atoms in a structure of a protein he designed.

Biochemist David Baker — just announced as a recipient of the Nobel Prize for Chemistry — turned to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory for information he couldn’t get anywhere else. HFIR is the strongest reactor-based neutron source in the United States.

In 2018, Baker designed a protein he thought could bind to amantadine, a drug used in the treatment of Parkinson’s disease. Baker’s new computationally designed amantadine-binding protein (ABP) is a potential control switch in targeted anti-cancer cell therapies. However, to confirm the complete structure and function of the assembled protein, a critical piece of information was missing. HFIR’s IMAGINE instrument delivered the missing piece (the location of hydrogen bonds in the ABP complex) through neutron scattering. This technique allowed Baker and his team to see hydrogen, a capability no other research technique can provide.

“Most people don’t quite understand why neutrons can be important,” said Dean Myles, a distinguished R&D scientist at ORNL. “In this particular case, the neutron experiment we did was critical to the science because they needed to know where the hydrogen atoms were. Neutrons are unique in that they can probe delicate samples or proteins without destroying them and allow us to find the hydrogen atoms. And as protein design and engineering advance, the positions of the hydrogen atoms will remain key to function.”

During a June workshop organized by ORNL’s Neutron Sciences Directorate, Linna An, a senior postdoctoral researcher from Baker’s lab, presented the lab’s vision for the future of computational structural biology and impacts in the field. The team’s next goal is enzyme design.

“Proton transfer is absolutely necessary information if we want to design enzymes, and neutron scattering is one of the key technologies to actually provide us this information,” An said.

Baker won one half of this year’s Nobel Prize in Chemistry for his work on proteins, which are made mainly from 20 amino acids. Most proteins in nature are created from some combination of these 20 amino acids. In principle, a limitless number of these combinations exists, and all of nature uses less than 0.1% of the possible combinations. Baker’s group is working on the other 99.9%. His premise is that we should use nature’s building blocks in new ways if we want new targeted drugs and better ways to get them where they are needed in the body.

“Essentially, this is about designer chemistry,” said Andrey Kovalevsky, distinguished R&D scientist at ORNL, who recently used neutrons to illuminate protein structures to aid drug design for aggressive cancers. “The million-dollar question is whether we can design an enzyme, a type of protein, from scratch and get it to do precisely the chemistry we want it to do. Baker and his colleagues have definitively answered the question and opened an incredible world of possibilities for new medicines.”

Science today brings solutions tomorrow

The ability to design proteins also opens doors for a range of other applications, such as streamlined vaccine development, a greener chemical industry and new nanomaterials. And since most enzymes are proteins, Baker’s work can also help improve everything from drug design to biofuel production, plastic decomposition and more.

“Biology holds enormous promise for life-saving breakthroughs and new technologies, and those discoveries will be possible in large part thanks to powerful research tools like HFIR,” ORNL Director Stephen Streiffer said. “It’s edifying to see this foundational ORNL capability, neutron scattering — which earned its own Nobel Prize in Physics — contribute to the work of new Nobel laureates. This is also a testament to HFIR’s long-standing and critical role across decades. Researchers who are leading new innovations can come to HFIR for answers.”

Baker relies primarily on advanced computing for protein structure design. Since the early 2000s, Baker, with the help of his research team based at the University of Washington, has been curating a databank, which now includes more than 200,000 protein structures he uses to create new proteins to help develop new medicines.

“David Baker used ORNL’s neutron scattering facilities to study hydrogen locations and bonds of his designer protein. It is, of course, fantastic and very rewarding to see scientific work recognized by the Nobel committee, and we are proud to have contributed to some of his studies with HFIR,” said Jens Dilling, associate laboratory director for Neutron Sciences at ORNL.

The June workshop, “Neutrons in Structural Biology,” held in Arlington, Virginia, provided a venue for structural biology and biochemistry experts, such as from Baker’s lab, early career researchers, and students to discuss scientific advances and collaboration opportunities, with an emphasis on new capabilities planned for ORNL’s Second Target Station (STS) at the Spallation Neutron Source (SNS). Instruments proposed for the STS will be capable of performing biological neutron crystallography on more complex systems than are possible today. SNS is the nation’s leading source of pulsed neutron beams for research.

“We cannot reliably predict where active hydrogen atoms sit and how chemistry is performed in many of these systems, which is why our biology user groups come to ORNL to use neutrons,” Myles said. “Workshops like this reconfirm for us how unique and in demand neutrons are, showcasing the power of neutrons in scientific discovery.”

Myles leads an IMAGINE research team funded by DOE’s Biopreparedness Research Virtual Environment (BRaVE) initiative, a program that bolsters DOE’s strategy for general biopreparedness and response to biological threats. Myles and his team have also designed an upgrade for IMAGINE that will enhance neutron analyses to collect data from radically smaller protein crystals, enabling faster therapeutic drug development. The upgrade increases signals from hydrogen atoms, making key features in protein structures more visible for efficient characterization.  — Sumner Brown Gibbs