RESEARCH: INFLUENZA
FOLDING PROJECT #18460 PROFILE

This project explores how miniproteins, tiny lab-designed proteins, bind to viruses like influenza. Researchers are using computer simulations to understand how changes in the miniprotein's structure affect its ability to block the virus. The goal is to design better miniprotein drugs that can fight infections more effectively.

Note: This TLDR is a simplication and may not be 100% accurate.

Designed miniproteins are a class of biomolecules with intermediate sizes—larger than small-molecule drugs, but smaller than monoclonal antibodies.

Miniproteins can be computationally designed to tightly bind protein targets for use as potential therapeutics, a promising new avenue for treating infectious disease. Hemagglutinin is a viral fusion protein that allows H1 influenza A (HA) to bind sialic acid on cell surfaces, as well as being involved in the post-endocytosis mechanism of cellular infection.

The Baker lab at University of Washington has developed de novo designed miniproteins that bind hemagglutinin, and improved their binding through affinity maturation (Chevalier et al.

2017).

Many of the mutations seen in affinity-matured sequences are not found in the binding interface, and it remains an open question how these changes lead to higher affinity.

Furthermore, many of the computational predictions of how single-point mutations affect binding deviate significantly from the experimentally determined values. Could all-atom molecular simulation approaches achieve more accurate predictions? In this set of simulations, we aim to use massively parallel expanded ensemble simulations to predict mutational effects on affinities to hemagglutinin.

By pairing these simulations with other simulations aimed at modeling the binding reactions of these miniproteins to hemagglutinin, we aim to have a relatively complete picture of a miniprotein-target binding reaction and how mutations affect it.

These studies are a large-scale investigation on how miniprotein binding reactions work in atomic detail, towards a better understanding of computational design and modulation of miniprotein therapeutics.

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miniproteins

Small proteins with therapeutic potential.

Miniproteins are engineered proteins designed for medical treatments. They are smaller than traditional antibodies but larger than small-molecule drugs. Their size allows them to target specific proteins in the body, making them promising candidates for treating various diseases.

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therapeutics

Substances used to treat or prevent disease.

Therapeutics are medical treatments designed to alleviate or cure diseases. They can include drugs, vaccines, gene therapies, and other interventions that target specific biological pathways or symptoms.

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hemagglutinin

Viral protein that binds to sialic acid on cell surfaces.

Hemagglutinin is a crucial viral protein found on the surface of influenza viruses. It allows the virus to attach to and enter human cells by binding to sialic acid molecules present on cell membranes. This interaction facilitates the spread of the infection within the body.

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affinity maturation

Process of improving antibody binding affinity.

Affinity maturation is a biological process that enhances the strength of an antibody's interaction with its target antigen. Through repeated cycles of mutations and selection, antibodies gradually evolve to bind their targets more tightly, leading to improved immune responses.

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molecular simulation

Computer-based modeling of molecular interactions.

Molecular simulation uses computational algorithms to model the behavior of molecules and their interactions. This technique allows researchers to study complex biological systems at an atomic level, providing insights into protein folding, drug binding, and other crucial processes.

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expanded ensemble simulations

Advanced simulation technique for studying complex systems.

Expanded ensemble simulations are a sophisticated computational method used to study biological systems with multiple energy states. By exploring a wider range of configurations, these simulations can provide more accurate predictions of protein folding, drug binding, and other dynamic processes.