RESEARCH: CANCER
FOLDING PROJECT #18453 PROFILE

This project looks at how tiny proteins fold into their shapes. They found a way to predict how changing the protein's code affects its folding, using powerful computer simulations. They want to test this method on bigger proteins like MeCP2, which is important for brain development and causes Rett syndrome when it's faulty.

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

The function of a protein depends on its native shape, or fold.

Deciphering the sequence-dependent process by which proteins reach their folded state has been the goal of much experimental and computational work, and the inspiration for the e Folding@home project.

Small “fast folding” mini-proteins, such as the protein G B1 domain (GB1) and hpin1 WW domain, have been studied extensively both experimentally and through simulation, producing a wealth of data on wild-type protein function, and much insight on how mutations affect the folding reaction.

In 2022, the Voelz lab published a study on the folding reaction of a transcription factor, FOXO1, in which a simple hydrophobic transfer model was used to accurately predict mutational effects from models derived from massively parallel Folding@home simulations (Novack et al.).

We found that this model made more accurate predictions than other state of the art methods of mutational analysis.

We hypothesize that this is because our simulations have more accurate descriptions of the unfolded ensemble of a protein than other methods, highlighting the importance of adequately describing the unfolded state of a protein in determining mutational effects on folding reaction.

In these projects, we aim to validate this hypothesis on the well studied miniproteins GB1 and hpin1 WW domain, as well as the MeCP2 protein.

MeCP2 is a protein that binds methylated DNA and is found in high levels in nerve cells.

the main disease associated with mutations of MeCP2 is Rett syndrome, a neurological disorder that severely impairs people’s ability to speak, walk, eat, and breathe.

The gene lives on X chromosomes, thus for people with an XY chromosomal configuration (lacking a complimentary natively functioning gene), this disease can be fatal within the first 2 years due to encephalopathy.

There are at least 4668 mutational variants of MeCP2 identified, with 1171 being in the only structured region of the protein, the MBD.

Stability effects of mutation in MeCP2 have been investigated both experimentally and computationally, which makes it a promising test case for both validation of hydrophobic transfer as a model of mutation effects, as well as an opportunity to gain atomic insight that can elucidate new avenues for therapeutics targeting MeCP2.

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protein

A large biomolecule composed of amino acids.

Proteins are essential molecules in all living organisms. They have a wide variety of functions, including catalyzing biochemical reactions, transporting molecules, and providing structural support. The shape and sequence of amino acids determine a protein's function.

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fold

The three-dimensional shape of a protein.

A protein's fold refers to its unique 3D structure. This shape is crucial for its function as it determines how the protein interacts with other molecules.

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mutation

A permanent alteration in the DNA sequence.

Mutations are changes in the genetic code. They can be spontaneous or caused by environmental factors. Some mutations have no effect, while others can alter protein function and lead to disease.

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transcription factor

A protein that binds to DNA and regulates gene expression.

Transcription factors are proteins that control which genes are turned on or off. They play a vital role in cellular processes by regulating gene expression.

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FOXO1

Forkhead box O1 transcription factor

FOXO1 is a protein that regulates various cellular processes, including growth, survival, and metabolism. It plays a role in aging and disease.

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MeCP2

Methyl-CpG binding protein 2

MeCP2 is a protein that binds to methylated DNA. It plays a crucial role in regulating gene expression in the brain.

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Rett syndrome

A rare genetic disorder that affects girls primarily.

Rett syndrome is a neurodevelopmental disorder that causes intellectual disability, autism spectrum disorder, and other neurological problems. It primarily affects females and is caused by mutations in the MECP2 gene.