RESEARCH: CANCER
FOLDING PROJECT #18412 PROFILE

This project uses computer simulations to predict how small changes in a protein's design can make it bind better to a bacterial target. By doing this, scientists hope to create new antibiotics that are more effective at fighting infections.

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 can help researchers understand complex biological processes and design new drugs.

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affinity-maturation

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

Affinity maturation is a technique used to enhance how strongly a protein binds to its intended target. It's often applied in drug development to create more effective medications.

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de novo designed

Proteins created from scratch using computational design.

De novo designed proteins are not found in nature. Scientists create them using computer algorithms to specify their structure and function.

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mini-proteins

Small proteins with specific binding capabilities.

Mini-proteins are compact versions of proteins that retain their ability to bind to specific targets. They're often used in drug development due to their small size and ease of production.

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binding affinity

The strength of the attraction between a molecule and its target.

Binding affinity describes how strongly a molecule, like a drug, attaches to its target, such as a protein. A higher binding affinity means a stronger interaction.

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periplasmic protease

An enzyme found in the periplasm of bacteria that degrades proteins.

Periplasmic proteases are enzymes located in the periplasm, a region between the cell membrane and cell wall of bacteria. They play a role in protein degradation and other cellular processes.

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LapG

L-Asparagine Peptidase G

LapG is a periplasmic protease involved in bacterial biofilm formation.

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biofilm

A community of bacteria encased in a self-produced matrix.

Biofilms are communities of bacteria that adhere to surfaces and form a protective layer around themselves. They can be found in various environments and pose challenges for human health and industry.

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antibiotic therapies

Treatments using antibiotics to combat bacterial infections.

Antibiotic therapies involve using drugs to kill or inhibit the growth of bacteria. They are essential for treating various bacterial infections.