RESEARCH: CANCER
FOLDING PROJECT #18425 PROFILE

This project uses computer simulations to predict how changing the design of mini-proteins will affect their ability to bind to a bacterial enzyme. The goal is to create better antibiotics by finding mini-proteins that block this enzyme and prevent bacteria from forming biofilms.

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 behavior.

Molecular simulation uses computer programs to mimic how atoms and molecules interact. This helps researchers understand chemical reactions, design new drugs, and predict material properties.

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affinity-maturation

Process of improving the binding affinity of a molecule to its target.

Affinity maturation is like fine-tuning a drug's ability to bind to its target. By making small changes to the drug's structure, scientists can increase its effectiveness and reduce side effects.

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de novo

From scratch; created anew.

De novo design means creating something entirely new, like designing a protein molecule from the ground up without relying on existing structures.

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protein binders

Molecules that bind to other proteins.

Protein binders are molecules that attach to specific proteins. This can be useful for developing drugs that block harmful protein activity or for creating diagnostic tools.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are compact versions of larger proteins that can still perform important tasks. They are often easier to design and produce than full-sized proteins.

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inhibitors

Substances that block the activity of other molecules.

Inhibitors are compounds that prevent or slow down chemical reactions. They are widely used in medicine to treat diseases by blocking the action of harmful proteins.

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LapG

Periplasmic protease involved in bacterial biofilm formation.

LapG is an enzyme produced by bacteria that helps them form biofilms. Biofilms are complex communities of bacteria that can be difficult to treat with antibiotics.

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antibiotic therapies

Medical treatments that use antibiotics to kill bacteria.

Antibiotic therapies are used to treat bacterial infections. Antibiotics work by interfering with the growth and reproduction of bacteria.