RESEARCH: CANCER
FOLDING PROJECT #18914 PROFILE

Lasso peptides are unique, ring-shaped molecules with potential as new medicines. This project uses computer simulations to understand how lasso peptides form their shape and how an enzyme called lasso peptide cyclase helps in this process. Learning about lasso peptide formation could lead to the development of new drugs for cancer, infections, and other diseases.

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

Lasso peptides are ribosomally synthesized and post-translationally modified peptide (RiPP) natural products that display a unique lariat-like, threaded conformation.

Some lasso peptides have been shown to bind human cell-surface receptors and exhibit anticancer properties, while others display antibacterial or antiviral bioactivities.

So studies on the lasso peptide synthesis will significantly facilitate the discovery and application of new drugs. Specifically, previous studies show that the unique lasso topology is formed by a macrolactam ring that is threaded by the C-terminal tail.

While not proven yet, the threading cannot occur after the ring formation.

The general proposed mechanism is that lasso peptide first form a prefolded lariat-like structure, then lasso peptide cyclase catalyzes the ring closure achieved by an isopeptide bond formed between the N-terminal α-amino group of a glycine, alanine, serine, or cysteine and the carboxylic acid side chain of an aspartate or glutamate, which can be located at positions 7, 8, or 9 of the amino acid sequence.

However, MD study on lasso peptide topology is very less and the detailed function of lasso peptide cyclase and the molecular mechanism of the whole lasso peptide cyclization process are not clear.

Therefore, in this study, we will perform Molecular Dynamic simulations for the system of lasso peptide or peptide with cyclase enzyme to explore lasso peptide topology and the cyclization mechanism.

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Lasso peptides

Ribosomally synthesized and post-translationally modified peptide natural products with a unique lariat-like conformation.

Lasso peptides are a special type of naturally occurring molecule made by bacteria. They have a distinct loop shape and show promise as new drugs because they can fight cancer, bacteria, and viruses. Scientists are still learning how these peptides are made and how they work.

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Ribosomally synthesized

Produced by ribosomes, the cellular machinery responsible for protein synthesis.

Ribosomes are tiny factories inside cells that make proteins. Ribosomally synthesized means something is made by these factories, like lasso peptides.

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Post-translationally modified

Chemical alterations made to a protein or peptide after its initial synthesis.

After a protein is made, sometimes it gets changed by adding or removing chemical groups. This process is called post-translational modification and helps proteins do their jobs.

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RiPP

Ribosomally synthesized and post-translationally modified peptides.

RiPP stands for ribosomally synthesized and post-translationally modified peptides. It's a shortcut way to describe these special types of molecules.

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Macrolactam ring

A large cyclic molecule formed by the reaction of a carboxylic acid and an amino group.

A macrolactam ring is like a big loop made from pieces of a protein. It's part of what gives lasso peptides their unique shape.

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Lasso peptide cyclase

An enzyme that catalyzes the formation of the macrolactam ring in lasso peptides.

Lasso peptide cyclase is a special protein that helps build the lasso shape by connecting specific parts of the molecule.

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Molecular Dynamic simulations

Computer simulations that model the movement of atoms and molecules over time.

Molecular Dynamic simulations are like computer games for scientists. They allow us to watch how molecules move and interact with each other.

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MD

Molecular Dynamic simulations.

MD stands for Molecular Dynamic simulations. It's a way to study how molecules move using computers.