RESEARCH: CANCER
FOLDING PROJECT #18451 PROFILE

This project studies how tiny proteins fold into their shapes and how changes to their code affect folding. They'll use computer simulations and experiments to understand this process in proteins like GB1, hpin1 WW domain, and MeCP2, which is linked to Rett syndrome.

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

Large biomolecule essential for various biological functions.

Proteins are complex molecules that perform many vital roles in living organisms. They act as catalysts, structural components, transport molecules, and more. Understanding protein structure and function is crucial for advancements in medicine and biotechnology.

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Fold

The three-dimensional shape of a protein.

The fold refers to the unique 3D structure that a protein adopts. This shape is crucial for its function as it determines how the protein interacts with other molecules. Protein folding is a complex process influenced by various factors.

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Mutation

A change in the DNA sequence.

Mutations are alterations in the genetic code (DNA). They can occur spontaneously or be induced by environmental factors. Some mutations are harmless, while others can lead to diseases or altered traits.

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Transcription Factor

A protein that regulates gene expression.

Transcription factors are proteins that control the process of gene transcription. They bind to specific DNA sequences and either activate or repress the expression of genes.

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FOXO1

Forkhead box O1 transcription factor.

FOXO1 is a specific type of transcription factor involved in regulating various cellular processes, including cell growth, metabolism, and stress response.

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MeCP2

Methyl-CpG-binding protein 2.

MeCP2 is a protein that binds to methylated DNA and plays a role in gene regulation. Mutations in the MeCP2 gene can cause Rett syndrome.

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Rett Syndrome

A rare neurodevelopmental disorder.

Rett syndrome is a severe neurological disorder primarily affecting females. It is characterized by developmental regression, intellectual disability, and repetitive hand movements.