RESEARCH: CANCER
FOLDING PROJECT #18417 PROFILE

This project uses computer simulations to predict how changing tiny parts of a protein can make it bind better to a bacteria target. The goal is to design new antibiotics that work more effectively by blocking the bacteria's ability to form biofilms.

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

The use of computer models to simulate molecular interactions.

Molecular simulation uses computer programs to mimic the behavior of molecules. This helps scientists understand how molecules interact with each other and their environment. It's used in various fields like drug discovery and materials science.

---

affinity maturation

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

Affinity maturation is like fine-tuning a molecular lock and key. Scientists use it to enhance the effectiveness of drugs by making them bind more strongly to their intended targets within the body.

---

mini-protein

A small protein with a defined function.

Mini-proteins are like compact versions of regular proteins. They have simpler structures but can still carry out important tasks. Researchers are exploring their use in drug development and other applications.

---

LapG

Lapsine G

LapG is a bacterial protein that plays a role in biofilm formation. Biofilms are communities of bacteria that can be resistant to antibiotics.

---

periplasmic protease

An enzyme located in the periplasm of bacteria that degrades proteins.

Periplasmic proteases are enzymes found in a specific region of bacteria called the periplasm. They break down proteins, playing a role in bacterial growth and defense.

---

biofilm

A community of microorganisms attached to a surface and enclosed in a self-produced matrix.

Biofilms are like cities for bacteria. They're communities of microbes that stick together on surfaces and create a protective shield. This makes them harder to treat with antibiotics.