RESEARCH: CANCER
FOLDING PROJECT #18409 PROFILE

This project uses computer simulations to predict how tiny protein changes can make them better at binding to a bacterial enzyme. This could lead to new, 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.

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molecular simulation

Using computer models to simulate molecular interactions.

Molecular simulation is a computational technique used to study the behavior of molecules and their interactions. It involves creating mathematical models of molecules and simulating their movements and interactions over time. This can be used to understand how drugs interact with target proteins, design new molecules with desired properties, and predict the outcome of chemical reactions.

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affinity maturation

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

Affinity maturation is a process used in drug development to enhance the strength of the interaction between a drug and its target. It involves making gradual changes to the drug's structure to increase its binding affinity, which leads to more effective drug action.

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mini-protein

A small protein with a defined function.

Mini-proteins are engineered proteins designed to be significantly smaller than traditional proteins while retaining their biological activity. They offer advantages in terms of production efficiency, stability, and targeted delivery.

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periplasmic protease

A protease enzyme located in the periplasm of bacteria.

Periplasmic proteases are enzymes found in the periplasm, a space between the cell membrane and the outer membrane of bacteria. They play various roles in bacterial physiology, including protein degradation, nutrient recycling, and defense against environmental stresses.

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LapG

A periplasmic protease involved in bacterial biofilm formation.

LapG is a specific type of periplasmic protease that has been identified as playing a key role in the formation of biofilms, which are complex communities of bacteria. It helps regulate the process by breaking down proteins within the biofilm.

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biofilm

A community of bacteria encased in a self-produced matrix.

Biofilms are communities of bacteria that adhere to surfaces and enclose themselves in a protective matrix composed of polysaccharides, proteins, and DNA. They are highly resistant to antibiotics and disinfectants, posing challenges for healthcare and industrial applications.

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antibiotic therapy

The use of antibiotics to treat bacterial infections.

Antibiotic therapy is a medical treatment that involves the administration of antibiotics to combat bacterial infections. Antibiotics work by inhibiting the growth or killing bacteria, thereby reducing the severity and duration of the infection.