RESEARCH: CANCER
FOLDING PROJECT #18404 PROFILE

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

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

Use of computer models to simulate molecular interactions.

Molecular simulation is a computational technique used to model the behavior of molecules and their interactions. This involves simulating atomic movements and forces over time to understand how molecules behave in different environments.

---

affinity maturation

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

Affinity maturation is a crucial step in drug development. It involves making small changes to a molecule's structure to enhance its ability to bind tightly to its intended target. This stronger binding often leads to improved drug efficacy.

---

mini-protein

Small protein with reduced complexity compared to full-sized proteins.

Mini-proteins are smaller versions of traditional proteins. They retain some functional properties but are simpler in structure and can be easier to produce and study. Mini-proteins have potential applications in drug development and other areas.

---

periplasmic protease

Enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes located in a specific region between the inner and outer membranes of bacteria. They play various roles in bacterial metabolism and survival, including degrading proteins and defending against antibiotics.

---

LapG

Leucine aminopeptidase G.

LapG is a specific type of periplasmic protease found in certain bacteria. It plays a role in biofilm formation and other processes.

---

biofilm

A structured community of microorganisms.

Biofilms are complex communities of microorganisms that adhere to surfaces and form protective layers. They can pose challenges in various fields, including medicine (causing infections) and industry (fouling equipment). Understanding biofilm formation is crucial for developing effective control strategies.