RESEARCH: CANCER
FOLDING PROJECT #18414 PROFILE

This project uses computer simulations to predict how changes to a mini-protein's design can improve its ability to bind to a bacterial target. This could lead to the development of new antibiotics that are more effective against bacteria.

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 uses computer programs to imitate how molecules interact and behave. This is helpful in fields like drug discovery to understand how drugs might bind to target proteins.

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affinity-maturation

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

Affinity maturation is like fine-tuning a drug's ability to bind to its target protein. Scientists make small changes to the drug's structure to increase its effectiveness and reduce side effects.

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de novo designed

Created from scratch using computational methods.

De novo design means creating something entirely new, in this case, designing a protein molecule from the ground up using computer algorithms.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are compact versions of traditional proteins that can still perform important tasks. They have potential as drugs because they are easier to produce and often more effective than larger proteins.

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inhibitors

Molecules that block the activity of other molecules.

Inhibitors are like molecular brakes. They prevent other molecules from doing their jobs, which can be useful for treating diseases by stopping harmful processes.

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binding affinity

The strength of the attraction between two molecules.

Binding affinity refers to how strongly a molecule can attach to another molecule. In drug development, high binding affinity is desirable because it means the drug will effectively target its intended protein.

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mutations

Changes in the DNA sequence.

Mutations are alterations in the genetic code. They can be caused by various factors and sometimes lead to changes in protein function, which is important for understanding how drugs work.

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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 region between the inner and outer membranes of bacteria. They play roles in various bacterial processes.

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LapG

The enzyme LapG is a periplasmic protease.

LapG is a protein that breaks down other proteins in bacteria. It's important for bacterial growth and survival.

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biofilm formation

The process by which bacteria attach to surfaces and form communities.

Biofilms are organized layers of bacteria that adhere to surfaces. They are resistant to antibiotics and play a role in various infections.

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antibiotic therapies

Medical treatments using antibiotics to fight bacterial infections.

Antibiotic therapies are used to treat bacterial infections by killing or inhibiting the growth of bacteria.