RESEARCH: CANCER
FOLDING PROJECT #18410 PROFILE

This project uses computer simulations to predict how changing the design of mini-proteins affects their ability to bind to a bacterial enzyme. 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.

.

---

molecular simulation

Simulation of molecular interactions using computational models.

Molecular simulation uses computer programs to mimic how molecules interact with each other. This is helpful in drug discovery as it allows scientists to test different molecule combinations virtually before conducting expensive and time-consuming lab experiments.

---

affinity maturation

A process of improving the binding affinity (strength) of a protein or antibody.

Affinity maturation is like fine-tuning a lock and key. Scientists start with a molecule that binds to its target (the lock), but they want it to bind even stronger. Through repeated rounds of testing and modifications, they 'mature' the molecule until it fits perfectly.

---

mini-proteins

Small proteins with specific functions.

Mini-proteins are like tiny versions of regular proteins. They're smaller and simpler, but they can still do important jobs, such as binding to other molecules or catalyzing reactions. Scientists use them in various applications, including drug development.

---

periplasmic protease

A type of enzyme found in the periplasm (space between the cell membrane and cell wall) of bacteria.

Periplasmic proteases are enzymes that break down proteins. They're important for various bacterial processes, such as breaking down nutrients or defending against invading molecules.

---

LapG

Protease LapG

LapG is a type of protease found in bacteria that plays a role in biofilm formation. Biofilms are communities of bacteria that attach to surfaces and can be difficult to treat with antibiotics.

---

biofilm

A community of microorganisms that adhere to a surface and are encased in a self-produced matrix.

Biofilms are like cities for bacteria. They form when bacteria attach to surfaces and create a protective layer around themselves. This makes them resistant to antibiotics and other treatments, making them a major problem in healthcare.