RESEARCH: CANCER
FOLDING PROJECT #18424 PROFILE

This project uses computer simulations to predict how small changes in a protein's design can improve its ability to block bacterial growth. The goal is to create new antibiotics by making existing designs more effective.

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 computers to mimic how molecules behave and interact. This is helpful in drug discovery to understand how drugs might bind to target proteins.

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affinity-maturation

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

Affinity maturation is like refining a drug's ability to stick to its target. Scientists make small changes to a drug's structure to increase how strongly it binds, leading to better effectiveness.

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de novo

Designed from scratch, not derived from existing molecules.

De novo design means creating something completely new. In protein design, it refers to building a protein molecule from the ground up, rather than modifying an existing one.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are like compact versions of regular proteins. They have a simpler structure and can often target specific biological processes efficiently.

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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) sticks to its target (like a protein). Higher affinity means a stronger bond.

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periplasmic protease

An enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes that break down proteins in a specific region called the periplasm, which surrounds the cell membrane of bacteria. They play a role in bacterial growth and survival.

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LapG

A periplasmic protease.

LapG is a specific type of bacterial enzyme that breaks down proteins in the periplasm. It's important for regulating bacterial biofilm formation.

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biofilm

A community of bacteria encased in a protective matrix.

Biofilms are like bacterial cities. They're formed when bacteria stick together and create a slimy coating around themselves. This makes them more resistant to antibiotics and other treatments.