RESEARCH: CANCER
FOLDING PROJECT #18419 PROFILE

This project tries to use computer simulations to design better mini-proteins that fight bacteria. Mini-proteins are small, lab-made proteins that can block harmful bacterial activity. The project aims to predict how changes in the mini-protein's design will affect its ability to bind to a specific bacterial target, helping scientists create more effective antibiotics.

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 using them to predict how they will behave under different conditions. This can be used to design new drugs, materials, and other products.

affinity maturation

The process of increasing the binding affinity of an antibody or protein.

Affinity maturation is a biological process that increases the strength of the interaction between an antibody and its target antigen. This is achieved through repeated rounds of mutation and selection, where antibodies with higher affinity are favored. Affinity maturation is crucial for the development of effective vaccines and therapeutic antibodies.

mini-protein

A small protein with a defined function.

Mini-proteins are short, engineered proteins that retain their biological activity despite their compact size. They offer advantages over traditional antibodies, such as lower production costs and improved tissue penetration. Mini-proteins have potential applications in various fields, including drug discovery, diagnostics, and biomaterials.

LapG

L.A.P. protease G.

LapG is a bacterial enzyme involved in biofilm formation. Biofilms are complex communities of bacteria that can resist antibiotics and host immune responses. Targeting LapG with inhibitors could be a potential strategy to combat bacterial infections.

periplasmic

Located in the periplasm.

The periplasm is a space between the inner and outer membranes of gram-negative bacteria. It contains various enzymes and proteins involved in transport, metabolism, and cell wall synthesis.