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Publications of the Week

De Novo Design of a Non-Local β-Sheet Protein with High Stability and Accuracy

By November 13, 2018No Comments

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This week we profile a recent publication in Nature Structural & Molecular Biology from
Dr. David Baker (pictured) at the Institute for Protein Design.

Can you provide a brief overview of your lab’s current research focus?

Natural proteins evolved over billions of years to solve biology’s most complex problems. But we face new and pressing challenges today. The goal of my lab at the UW Institute for Protein Design is to develop and apply methods for designing a whole new world of synthetic proteins to address 21st-century challenges in precision medicine, energy production, manufacturing, and more.

We combine computer science and molecular biology to design novel proteins from first principles that can serve as medicines, vaccines, catalysts, biomaterials, sensors, and beyond. We have assembled and collaborate with top experts in protein science, computer science, biochemistry and biological structure, pharmacology, immunology, and clinical medicine.

Right now we are most focused on designing from scratch smart cancer therapies, living computers, new drug delivery vehicles, and self-assembling nanomaterials.

What is the significance of the findings in this publication?

All proteins are built from the same basic structural parts — helices, sheets, and loops — but certain combinations are more complex to design than others. In particular, proteins made entirely of beta strands and loops have proven challenging. Such proteins are very important in biology and human health. They include antibodies, for example.

This week we published the successful design of the first complex all-beta strand proteins. These new proteins have non-local beta strand interactions, meaning it was essential to control both the fine features (such as hydrogen bonding) and global features (such as the interwoven topology) of the proteins. We are very excited to have made progress on this challenging front.

What are the next steps for this research?

As de novo protein design matures through this and other milestones, we are moving closer to a time when custom proteins with designed shapes and functions can be computationally generated from first principles. This means that instead of discovering and modifying biomolecules that happen to exist in nature — a Stone Age approach to tool building — we will be able to design the biotechnologies we want from first principles. The sky’s the limit.

If you’d like us to mention your funding sources, please list them.

We are grateful to be funded by the NSF, NIH, DoD, the state of Washington, and many other governmental sources. We are also supported by the generosity of many non-governmental foundations and philanthropies, including the Bill & Melinda Gates Foundation and the Open Philanthropy Project.

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