RESEARCH: CANCER
FOLDING PROJECT #18421 PROFILE

This project uses computer simulations to predict how changes in a mini-protein's design will affect its ability to bind to a bacterial protein. The goal is to create better antibiotics by finding mini-proteins that can block the target protein 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

Using computer models to simulate molecular interactions.

Molecular simulation uses computer programs to mimic how atoms and molecules interact. This helps scientists understand chemical reactions, design new materials, and study biological processes.

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affinity-maturation

A process of improving the binding affinity (strength) of a molecule to its target.

Affinity maturation is like fine-tuning a molecular key to fit a lock perfectly. Scientists use it to create drugs that bind more strongly to their targets, making them more effective.

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de novo

Latin for 'from new'; used to describe the design of something entirely from scratch.

De novo means designing something completely new. In protein engineering, it refers to creating proteins from scratch based on computer models.

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protein binders

Molecules that bind specifically to target proteins.

Protein binders are like molecular handcuffs that attach to specific proteins. This can be used to block harmful protein activity or activate beneficial ones.

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mini-proteins

Small proteins with a defined function.

Mini-proteins are like compact versions of regular proteins. They often have specific functions and can be easier to design and produce.

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periplasmic protease

A type of enzyme found in the periplasmic space of bacteria.

Periplasmic proteases are enzymes that break down proteins. They are located in a specific region between the inner and outer membranes of bacteria.

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LapG

A bacterial protein involved in biofilm formation.

LapG is a specific protein that helps bacteria build biofilms. Biofilms are communities of bacteria that can be resistant to antibiotics.

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biofilm

A structured community of microorganisms.

A biofilm is like a city for bacteria. They attach to surfaces and create a protective layer around themselves.

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antibiotic therapies

Treatments using antibiotics to fight bacterial infections.

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