RESEARCH: CANCER
FOLDING PROJECT #18408 PROFILE

This project uses computer simulations to predict how changes to a mini-protein's design affect its ability to bind to a bacterial protein. The goal is to find better ways to block this bacterial protein, which helps bacteria form harmful biofilms. This could lead to new and more effective antibiotics.

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

Using computer models to simulate molecular interactions.

Molecular simulation is a technique used in biotechnology and drug discovery to understand how molecules interact at the atomic level. It involves creating computer models of molecules and simulating their behavior over time. This can be used to predict how drugs might bind to target proteins or how different chemical compounds might interact with each other.

---

affinity-maturation

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

Affinity maturation is a crucial step in developing effective drugs. It involves modifying the structure of a protein (often an antibody) to increase its ability to bind tightly to a specific target molecule. This enhanced binding makes the drug more potent and effective.

---

de novo designed

Created from scratch using computational design.

De novo design refers to the creation of new proteins or molecules from the ground up, rather than modifying existing ones. This process often involves computer algorithms that predict the structure and function of potential designs.

---

mini-proteins

Small proteins with specific functions.

Mini-proteins are compact versions of traditional proteins that retain their biological activity. These smaller proteins can be easier to produce and manipulate, making them attractive for various applications, such as drug development.

---

periplasmic protease

An enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes located within the periplasm, a space between the inner and outer membranes of bacteria. They play various roles, including breaking down proteins and regulating cellular processes.

---

LapG

A specific type of periplasmic protease.

LapG is a bacterial protein that functions as a protease in the periplasm. It plays a role in regulating biofilm formation, which is essential for bacterial survival and pathogenesis.

---

biofilm

A community of bacteria encased in a protective matrix.

Biofilms are complex communities of microorganisms that adhere to surfaces and enclose themselves within a self-produced extracellular matrix. This matrix provides protection from environmental stresses and antibiotics, making biofilms difficult to eradicate.

---

antibiotic therapies

Medical treatments using antibiotics to fight bacterial infections.

Antibiotic therapies are essential for treating bacterial infections. Antibiotics work by targeting specific processes within bacteria, such as cell wall synthesis or protein production, ultimately killing the bacteria.