RESEARCH: CANCER
FOLDING PROJECT #18413 PROFILE

This project uses computer simulations to predict how changes to a mini-protein's design can improve its ability to bind to a bacterial enzyme. By making these predictions, scientists hope to develop new antibiotics that are more effective at fighting bacterial infections.

Note: This TLDR is a simplication and may not be 100% accurate.

Can molecular simulation be used for virtual affinity-maturation of de novo designed protein binders? That’s the question this project aims to address.

The Bahl Lab at the Institute for Protein Innovation has had some amazing success using computational design to develop high-affinity mini-proteins that can inhibit protein targets by tightly binding to them.

In practice, the current approach requires the experimental screening of thousands of computational designs to discover a few tight binders, and similarly expensive experimental screens to optimize their binding (i.e.

“affinity maturation”).

If we can make more accurate predictions of how sequence mutations affect binding affinity, we may be able to offload this expensive task to computers, boosting the efficiency of these efforts considerably. In this project, we use relative free energy calculations to predict how single-point mutations of a computationally designed mini-protein alter the binding affinity to the periplasmic protease LapG, an important regulator of bacterial biofilm formation.

These predictions will be compared to high-throughput experimental measurements of binding affinity provided by the Bahl lab.

An important end goal of this work is to develop new classes of inhibitors to make antibiotic therapies more successful.

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molecular simulation

Use of computer models to simulate molecular interactions.

Molecular simulation uses computer programs to imitate how molecules interact with each other. This is helpful for understanding chemical reactions and designing new drugs.

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affinity maturation

The process of improving the binding affinity of a molecule to its target.

Affinity maturation is like refining a drug's ability to latch onto its target. Researchers tweak the drug's structure until it binds more strongly and effectively.

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mini-protein

Small proteins with specific functions.

Mini-proteins are like compact versions of regular proteins. They're smaller but still do important jobs, making them useful for things like drug development.

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LapG

Periplasmic protease LapG

LapG is a bacterial enzyme that plays a role in biofilm formation. Biofilms are communities of bacteria that can be difficult to treat with antibiotics.

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biofilm

A community of microorganisms that adhere to a surface and are encased in a matrix.

Biofilms are like bacterial cities. They're communities of bacteria that stick together and form a protective layer. This makes them harder to treat with antibiotics.

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antibiotic therapies

The use of antibiotics to treat bacterial infections.

Antibiotic therapies are treatments that use medicines called antibiotics to fight bacterial infections.