RESEARCH: CANCER
FOLDING PROJECT #18402 PROFILE

This project uses computer simulations to see how changing the design of tiny proteins can make them bind better to a bacterial target. This could lead to new, 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 behavior.

Molecular simulation uses computer programs to imitate how atoms and molecules interact. This helps scientists understand chemical reactions, predict protein folding, and design new drugs.

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affinity maturation

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

Affinity maturation is like fine-tuning a key to fit a lock better. Scientists use this process to create drugs that bind more strongly to their target proteins, making them more effective.

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mini-protein

A small protein with a specific function.

Mini-proteins are tiny versions of regular proteins. They have the same ability to bind to other molecules, but they are much smaller and easier to produce.

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periplasmic protease

An enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes that break down proteins. They are located in a space between the cell membrane and the outer membrane of bacteria.

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bacterial biofilm

A community of bacteria that live together in a slimy matrix.

Bacterial biofilms are like cities for bacteria. They form on surfaces and are very difficult to kill because the bacteria are protected by their sticky matrix.

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antibiotic therapies

Treatments that use antibiotics to kill or inhibit the growth of bacteria.

Antibiotic therapies are used to treat bacterial infections. They work by killing or stopping the growth of bacteria.