RESEARCH: CANCER
FOLDING PROJECT #18415 PROFILE

This project explores using computer simulations to design better antibiotics. Researchers are trying to predict how tiny changes to protein structures can improve their ability to block harmful bacteria from forming biofilms, a major obstacle to antibiotic treatments.

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

The use of computer models to simulate molecular interactions.

Molecular simulation uses computer programs to mimic how molecules interact with each other. This can be used to study the behavior of proteins, DNA, and other biomolecules, which is helpful for drug discovery and understanding biological processes.

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affinity maturation

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

Affinity maturation is like fine-tuning a protein's ability to latch onto its target molecule. It involves making small changes to the protein's structure to increase its strength of binding. This is important in drug development because it can lead to more effective therapies.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are like compact versions of regular proteins. They have fewer amino acids but can still perform important tasks. Their small size makes them attractive for drug development because they can be easier to produce and deliver.

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binding affinity

The strength of the attraction between a protein and its target molecule.

Binding affinity describes how strongly a protein sticks to its target. The higher the affinity, the tighter the bond. This is crucial in drug development because drugs need to bind strongly to their targets to be effective.

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periplasmic protease

An enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes that break down proteins within the periplasm, a space between the cell membrane and the outer membrane of bacteria. They play important roles in bacterial growth and survival.

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LapG

Leucine aminopeptidase G.

LapG is a specific type of periplasmic protease found in some bacteria. It plays a role in breaking down proteins and is involved in bacterial biofilm formation.

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bacterial biofilm

A community of bacteria encased in a protective matrix.

Bacterial biofilms are like cities for bacteria. They're communities of bacteria that stick together and form a protective layer around themselves. This makes them resistant to antibiotics and other treatments, making them a challenge for healthcare.