RESEARCH: CANCER
FOLDING PROJECT #18416 PROFILE

This project uses computer simulations to predict how changes to a mini-protein can make it bind more strongly to a bacteria target. The goal is to design better antibiotics by creating proteins that block bacterial growth.

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

Using computer models to simulate molecular interactions.

Molecular simulation is a powerful technique used in biotechnology and pharmacology to understand how molecules interact at the atomic level. Researchers use computer algorithms to model these interactions, allowing them to predict the behavior of molecules in various environments and conditions.

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affinity-maturation

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

Affinity maturation is a crucial step in drug development where researchers aim to enhance the binding strength between a drug molecule and its intended target. This involves making subtle changes to the drug's structure, guided by experimental data and computational modeling, to optimize its interaction with the target.

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de novo

From scratch; newly created.

De novo refers to the design and creation of biological molecules, such as proteins or DNA sequences, from scratch. This involves using computational tools and knowledge of molecular structure and function to build novel biomolecules with desired properties.

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mini-proteins

Small proteins with specific functions.

Mini-proteins are small, engineered proteins designed to perform specific biological tasks. These compact molecules offer advantages over traditional antibodies, such as improved stability and tissue penetration, making them promising candidates for therapeutic applications.

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binding affinity

The strength of the interaction between two molecules.

Binding affinity describes how strongly a molecule, such as a drug or antibody, binds to its target. High binding affinity indicates a strong interaction, essential for effective therapeutic action.

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single-point mutations

Changes in a single nucleotide within a DNA sequence.

Single-point mutations involve altering a single nucleotide base pair within a DNA sequence. These changes can have diverse effects on protein structure and function, making them valuable tools for studying gene regulation and protein evolution.

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periplasmic protease

A type of enzyme found in the periplasm of bacteria.

Periplasmic proteases are enzymes located in the periplasm, a space between the cell membrane and the outer membrane of certain bacteria. These proteases play crucial roles in bacterial physiology, including protein degradation, nutrient acquisition, and defense mechanisms.

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biofilm formation

The process by which bacteria attach to surfaces and form communities.

Biofilm formation is a complex process where bacteria adhere to surfaces, multiply, and produce a protective matrix that encases the community. Biofilms are highly resilient structures that play a role in bacterial pathogenesis, antibiotic resistance, and environmental persistence.

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antibiotic therapies

Treatments using antibiotics to fight bacterial infections.

Antibiotic therapies are essential for treating bacterial infections. These treatments involve administering medications that target and kill or inhibit the growth of bacteria.