RESEARCH: CANCER
FOLDING PROJECT #18403 PROFILE

This project uses computer simulations to predict how changes to a mini-protein can make it bind more strongly to a bacteria target. This could help scientists design better antibiotics.

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

Computer modeling of molecular interactions.

Molecular simulation uses computer programs to mimic the behavior of molecules. This is valuable in drug discovery because it allows scientists to test how different molecules interact before conducting expensive and time-consuming lab experiments.

affinity maturation

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

Affinity maturation is like fine-tuning a lock and key. Scientists start with a protein that binds to its target (the 'lock'), but it might not be very strong. Through iterative rounds of mutations and testing, they gradually improve the fit until the protein binds tightly (like a well-made key).

mini-protein

A small protein with a specific function.

Mini-proteins are like compact versions of regular proteins. They are designed to be smaller and more stable, making them useful for various applications like drug delivery or targeting specific diseases.

LapG

L-Aspartic acid peptidase G

LapG is a bacterial enzyme that plays a crucial role in biofilm formation. Biofilms are communities of bacteria that attach to surfaces and can cause infections that are difficult to treat.

biofilm

A community of microorganisms attached to a surface.

Biofilms are like bacterial cities. They consist of millions of bacteria encased in a protective matrix that shields them from antibiotics and the immune system. This makes infections caused by biofilms very challenging to treat.