RESEARCH: CANCER
FOLDING PROJECT #18405 PROFILE

This project uses computer simulations to predict how changes to mini-proteins affect their ability to bind to a bacterial enzyme (LapG). By making more accurate predictions, researchers hope to design better antibiotics and make treatments more effective.

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

Using computer models to simulate molecular interactions.

Molecular simulation uses computer programs to mimic how molecules interact with each other. This helps researchers understand chemical reactions, design new materials, and study biological processes.

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Affinity maturation

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

Affinity maturation is like fine-tuning a lock and key. It involves making small changes to a molecule (the 'key') so that it binds more strongly to its target (the 'lock'). This is important in drug development, as molecules with higher affinity are more effective.

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De novo designed protein binders

Proteins created from scratch using computer design.

De novo designed protein binders are brand new proteins built from the ground up using computer software. Researchers can program these proteins to have specific shapes and functions, making them useful for things like drug delivery or sensing.

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Mini-proteins

Small proteins with specific functions.

Mini-proteins are like tiny versions of regular proteins. They're small enough to be easy to make and study, but they can still do important jobs like binding to other molecules or catalyzing reactions.

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Periplasmic protease

A type of enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes that break down proteins. They're located in the periplasm, a space between the inner and outer membranes of bacteria. These enzymes play important roles in bacterial metabolism and defense.

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LapG

Leptospirilla protein G protease (an enzyme)

LapG is a specific type of bacterial enzyme that helps control biofilm formation. Biofilms are communities of bacteria that stick together and protect themselves from the environment.

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Biofilm formation

The process by which bacteria attach to surfaces and form communities.

Biofilm formation is like bacteria building a city. They stick together on surfaces and create a protective layer around themselves. This makes them harder to treat with antibiotics.

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Antibiotic therapies

Treatments that use drugs to kill or inhibit the growth of bacteria.

Antibiotic therapies are used to treat bacterial infections. These medications work by killing or slowing down the growth of bacteria in the body.