RESEARCH: CANCER
FOLDING PROJECT #12432 PROFILE

This project studies how proteins fold into their shapes and how changes in the protein's code affect its folding. They'll use computer simulations to understand this process in mini-proteins and a protein called MeCP2, which is important for brain function and mutations can cause 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

A large biomolecule consisting of chains of amino acids.

Proteins are essential building blocks of life. They perform a wide range of functions within cells and organisms, including catalyzing biochemical reactions, transporting molecules, providing structural support, and regulating gene expression.

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fold

The three-dimensional shape of a protein.

A protein's fold determines its function. It is the unique arrangement of amino acids that allows proteins to interact with other molecules and carry out specific tasks.

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transcription factor

A protein that binds to DNA and regulates gene expression.

Transcription factors are essential for controlling which genes are turned on or off in a cell. They play a crucial role in development, cell differentiation, and response to environmental stimuli.

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mutation

A permanent change in the DNA sequence.

Mutations can be caused by errors during DNA replication or exposure to mutagens. They can have various effects on an organism, ranging from harmless to harmful.

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Rett syndrome

A rare neurological disorder that primarily affects girls.

Rett syndrome is characterized by developmental regression, intellectual disability, and repetitive behaviors. It is caused by mutations in the MECP2 gene.

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MBD

Methyl-binding domain

The MBD is a protein domain that binds to methylated DNA.