RESEARCH: CANCER
FOLDING PROJECT #18931 PROFILE

Lasso peptides are special molecules with a unique shape that could be used to make new drugs. This project will use computer simulations to learn how lasso peptides are made and figure out how their shape helps them work.

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 structure.

Lasso peptides are a special type of naturally occurring molecule made by ribosomes. They have a distinctive shape resembling a lasso due to a loop formed within the molecule. These peptides exhibit diverse biological activities, including anticancer, antibacterial, and antiviral properties, making them attractive targets for drug development.

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Ribosomally synthesized

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

Ribosomally synthesized means that a molecule is made by ribosomes. Ribosomes are complex structures within cells that act as factories, assembling proteins according to instructions from DNA. Many important biomolecules, including peptides and proteins, are produced this way.

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Post-translationally modified

Chemical alterations made to a protein after its initial synthesis by ribosomes.

Post-translationally modified means that changes are made to a protein molecule after it has been initially built. These modifications can alter the protein's function, location, or interactions with other molecules, playing crucial roles in cellular processes.

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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 category of natural products derived from microorganisms with diverse biological activities.

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Macrolactam ring

A cyclic structure formed by a lactam bond between an amino group and a carboxylic acid group within a peptide.

A macrolactam ring is a large ring-shaped structure found in certain peptides. It's formed when an amino group (NH2) and a carboxylic acid group (COOH) within the same molecule react, creating a special bond called a lactam bond.

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Isopeptide bond

A peptide bond formed between a side chain of an amino acid and the carboxyl group of another amino acid.

An isopeptide bond is a specific type of chemical link found within proteins. It connects the side chain (R-group) of one amino acid to the carboxyl group (-COOH) of another amino acid. These bonds are important for protein structure and function.

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Molecular Dynamic simulations

Computer-based methods used to simulate the movement and interactions of atoms and molecules over time.

Molecular Dynamic simulations are powerful tools used in computational biology. They involve using computers to model the movements and interactions of atoms within molecules over time. This allows scientists to study how molecules behave, interact, and change shape.