RESEARCH: CANCER
FOLDING PROJECT #18407 PROFILE

This project uses computer simulations to predict how changes to a mini-protein can make it bind better to a bacterial target. The goal is to develop new antibiotics by making more effective protein inhibitors.

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

Use of computer models to simulate molecular interactions.

Molecular simulation uses computer programs to mimic how atoms and molecules interact. This helps scientists understand how drugs work, design new ones, and predict their effectiveness.

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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 drug's ability to stick to its target. Scientists make small changes to the drug's structure to increase how strongly it binds, making it more effective.

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de novo designed

Created from scratch using computational methods.

De novo designed means creating something entirely new. In this case, scientists use computer programs to design proteins from the ground up, without relying on existing ones.

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protein binders

Proteins that bind specifically to other molecules.

Protein binders are like tiny magnets that latch onto specific targets. They're crucial for many biological processes and have potential in drug development.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are like compact versions of regular proteins. They're smaller and often have simpler structures, making them easier to design and study.

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LapG

Periplasmic protease involved in bacterial biofilm formation.

LapG is a protein found in bacteria that helps them build biofilms. Biofilms are communities of bacteria that stick to surfaces and can be difficult to treat with antibiotics.

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binding affinity

The strength of the interaction between two molecules.

Binding affinity describes how tightly two molecules stick together. A higher binding affinity means a stronger interaction.