RESEARCH: CANCER
FOLDING PROJECT #18406 PROFILE

This project explores using computer simulations to design better mini-proteins that fight bacteria. By predicting how small changes to these proteins affect their ability to bind to a bacterial target, researchers hope to create 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

Using computer models to simulate molecular interactions.

Molecular simulation is a computational technique that uses computer models to simulate the behavior of molecules and their interactions. It's used in various fields, including drug discovery, materials science, and biochemistry, to understand how molecules behave at an atomic level.

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affinity maturation

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

Affinity maturation is a crucial process in drug development where scientists aim to enhance the binding strength between a drug molecule and its target. This can be achieved through iterative rounds of mutagenesis and selection, resulting in molecules with improved efficacy and reduced side effects.

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mini-protein

Small, engineered proteins with specific functions.

Mini-proteins are short, synthetically designed proteins that possess defined biological activities. They offer several advantages over traditional antibodies, including smaller size, faster production, and improved stability, making them promising candidates for therapeutic applications.

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periplasmic protease

A type of enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes that reside in the periplasm, a space between the inner and outer membranes of gram-negative bacteria. They play various roles in bacterial physiology, including protein degradation, nutrient processing, and virulence.

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LapG

L-asparaginase G protease

LapG is a specific type of protease found in certain bacteria. It plays a role in bacterial biofilm formation, which is the process by which bacteria adhere to surfaces and create communities.

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biofilm

A community of microorganisms that adhere to surfaces and each other.

Biofilms are complex communities of microorganisms that attach to surfaces and form protective layers. They are found in various environments, including medical devices, aquatic ecosystems, and even within the human body. Biofilms can be challenging to treat due to their resistance to antibiotics and host immune responses.

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antibiotic therapies

Medical treatments using antibiotics to combat bacterial infections.

Antibiotic therapies are essential for treating bacterial infections. Antibiotics work by targeting specific mechanisms within bacteria, inhibiting their growth or causing cell death. However, the emergence of antibiotic resistance poses a significant threat to global health.