RESEARCH: CANCER
FOLDING PROJECT #18411 PROFILE

This project uses computer simulations to predict how changing tiny parts of a protein designed to block bacterial growth will affect its ability to bind to bacteria. By comparing these predictions to real experiments, researchers hope to develop new and more effective antibiotics.

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

Simulating molecular interactions using computers.

Molecular simulation uses computer models to mimic how atoms and molecules interact. This helps scientists understand chemical reactions, design new materials, and study biological processes like protein folding.

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affinity-maturation

The process of improving the binding affinity of a protein or drug molecule.

Affinity maturation is like fine-tuning a molecular lock and key. Scientists modify a protein or drug to bind more strongly to its target, making it more effective.

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de novo designed

Created from scratch using computational methods.

De novo designed proteins are built from the ground up using computer algorithms. This allows scientists to create novel proteins with specific functions.

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protein binders

Proteins that bind specifically to other molecules.

Protein binders are like molecular magnets, attaching to specific targets. They have important roles in drug development and biological processes.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are compact versions of regular proteins. They offer advantages in drug development due to their size and stability.

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periplasmic protease

An enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes located in the space between the inner and outer membranes of bacteria. They play roles in various cellular processes, including protein degradation.

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LapG

Protease LapG.

LapG is a protease enzyme involved in regulating bacterial biofilm formation.

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antibiotic therapies

Medical treatments using antibiotics to fight bacterial infections.

Antibiotic therapies are essential for treating bacterial infections. They work by killing or inhibiting the growth of bacteria.

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biofilm formation

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

Biofilm formation allows bacteria to create protective layers that resist antibiotics and host immune systems. This makes infections harder to treat.