RESEARCH: CANCER
FOLDING PROJECT #18423 PROFILE

This project uses computer simulations to predict how changes to a mini-protein's design will affect its ability to bind to a bacterial protein. The goal is to create better antibiotics by designing mini-proteins that block bacterial growth.

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

Simulations of molecular behavior using computer models.

Molecular simulation uses computer programs to mimic the interactions between atoms and molecules. This helps researchers understand how molecules behave in different environments and predict their properties.

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affinity maturation

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

Affinity maturation is a crucial step in drug development where scientists enhance the ability of a drug molecule (like an antibody) to bind strongly and specifically to its intended target.

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mini-protein

Small proteins with specific functions.

Mini-proteins are smaller versions of traditional proteins, often designed for specific tasks like binding to target molecules or catalyzing reactions. Their compact size allows for easier production and manipulation.

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periplasmic protease

An enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes located in the periplasm, a space between the cell membrane and the outer membrane of some bacteria. They play roles in protein degradation and other cellular processes.

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biofilm

A community of microorganisms attached to a surface.

Biofilms are communities of bacteria or other microbes that adhere to surfaces and enclose themselves in a protective matrix. This makes them more resistant to antibiotics and disinfectants.

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LapG

Leucine aminopeptidase G.

LapG is a type of enzyme (leucine aminopeptidase) found in bacteria. It plays a role in the breakdown of proteins and is involved in biofilm formation.

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antibiotic therapy

Treatment of bacterial infections using antibiotics.

Antibiotic therapy is the use of medications to treat bacterial infections. Antibiotics work by killing or inhibiting the growth of bacteria.