RESEARCH: CANCER
FOLDING PROJECT #18422 PROFILE

This project uses computer simulations to predict how changes in a mini-protein's design affect its ability to bind to a bacterial enzyme. The goal is to develop new, more effective antibiotics by designing mini-proteins that block the enzyme and prevent bacteria from forming biofilms.

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 imitate how atoms and molecules interact. This helps scientists understand chemical reactions, design new drugs, and predict the properties of materials.

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affinity maturation

A process of improving the binding affinity of a molecule, such as an antibody.

Affinity maturation is like fine-tuning a lock and key. Scientists use this process to make molecules bind more strongly to their targets. This is important for developing better drugs and therapies.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are like compact versions of regular proteins. They can have important jobs in the body and are being studied for their potential use in medicine.

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LapG

A periplasmic protease.

LapG is a bacterial enzyme that breaks down proteins. It plays a role in the formation of biofilms, which are communities of bacteria that can be difficult to treat with antibiotics.

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periplasmic

Located in the periplasm, the space between the cell membrane and the outer membrane of bacteria.

The periplasm is a region within bacteria. It's like a small pocket between two layers of the bacterial cell wall. Periplasmic proteins have important jobs in processes like nutrient uptake and waste removal.

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biofilm

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

Biofilms are like cities for bacteria. They are groups of bacteria that stick together and create a protective layer around themselves. This makes them harder to treat with antibiotics.