RESEARCH: CANCER
FOLDING PROJECT #18420 PROFILE

This project aims to use computer simulations to predict how changes to a mini-protein's design will affect its ability to bind to a bacterial enzyme. By making these predictions, we hope to speed up the process of finding new 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 involves using computer programs to mimic the movements and interactions of atoms and molecules. This technique is widely used in biotechnology and pharmacology to study chemical reactions, protein folding, and drug-target binding.

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affinity maturation

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

Affinity maturation is a crucial step in drug development. It involves making small changes to a molecule's structure to enhance its ability to bind to its intended target (e.g., a protein). This increased binding affinity leads to more effective drugs.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are smaller versions of traditional proteins that often retain their functional capabilities. They have gained attention in biotechnology due to their potential applications in drug discovery, diagnostics, and therapeutics.

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LapG

Leptospira interrogans protease G

LapG is a bacterial enzyme involved in the formation of biofilms. Biofilms are communities of bacteria that adhere to surfaces and can cause infections.

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periplasmic protease

A protease found in the periplasm of bacteria.

Proteases are enzymes that break down proteins. Periplasmic proteases are located in the periplasm, a space between the cell membrane and the outer membrane of bacteria. They play various roles in bacterial metabolism and defense.

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antibiotic therapies

Medical treatments using antibiotics to fight bacterial infections.

Antibiotic therapies are essential for treating bacterial infections. These therapies involve the use of medications that kill or inhibit the growth of bacteria.