RESEARCH: CANCER
FOLDING PROJECT #18418 PROFILE

This project uses computer simulations to predict how changes in a mini-protein's design affect its ability to bind to a bacterial target. The goal is to develop more effective antibiotics by designing proteins that block bacteria from forming harmful biofilms. This could make current antibiotic treatments more successful.

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.

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molecular simulation

Use of computer models to simulate molecular behavior

Molecular simulation uses computer algorithms to mimic how atoms and molecules interact. This allows scientists to study chemical reactions, protein folding, and other biological processes without needing expensive or time-consuming laboratory experiments.

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affinity maturation

Process of improving the binding affinity of a molecule to its target

Affinity maturation is a process used in drug development to improve how well a drug binds to its intended target. This often involves making small changes to the drug's structure through repeated rounds of testing and refinement.

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mini-protein

Small protein with a specific function

Mini-proteins are compact versions of naturally occurring proteins that have been designed for specific tasks. They often exhibit high stability and can be easily produced in large quantities, making them valuable tools in drug development and other applications.

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LapG

Periplasmic protease from _E. coli_

LapG is a bacterial enzyme that plays a role in biofilm formation by breaking down proteins within the cell's outer membrane. Understanding LapG can help researchers develop new antibiotics.

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periplasmic protease

Enzyme found in the periplasm of bacteria

Periplasmic proteases are enzymes that break down proteins within the periplasm, a space between the cell membrane and the outer membrane of gram-negative bacteria. They play important roles in bacterial metabolism, virulence, and antibiotic resistance.

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biofilm

Structured community of microorganisms

A biofilm is a complex community of microorganisms that adhere to a surface and are encased in a protective matrix. Biofilms can form on various surfaces, including medical devices, rocks, and living tissues. They are often associated with antibiotic resistance and chronic infections.