RESEARCH: CANCER
FOLDING PROJECT #12433 PROFILE

The project relates to understanding how proteins fold into their correct shapes. This is important because a protein's shape determines its function. Researchers are using computer simulations to study how changes in a protein's code affect its folding. They're focusing on mini-proteins and MeCP2, a protein linked to Rett syndrome, a serious neurological disorder.

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.

---

protein

A large biomolecule composed of amino acids.

Proteins are essential molecules in living organisms that perform a wide range of functions, including catalyzing biochemical reactions, transporting molecules, providing structural support, and regulating cellular processes.

---

fold

The three-dimensional shape of a protein.

The fold of a protein is crucial for its function. The specific arrangement of amino acids determines how the protein interacts with other molecules and performs its role.

---

mutation

A permanent change in the DNA sequence.

Mutations can alter protein structure and function. Some mutations are harmless, while others can lead to disease.

---

transcription factor

A protein that binds to DNA and regulates gene expression.

Transcription factors play a critical role in controlling which genes are turned on or off. They can activate or repress the transcription of DNA into RNA.

---

FOXO1

Forkhead box O1 transcription factor.

FOXO1 is a transcription factor involved in various cellular processes, including cell growth, differentiation, and survival. Mutations in FOXO1 can contribute to the development of diseases such as cancer.

---

MeCP2

Methyl-CpG-binding protein 2.

MeCP2 is a protein that binds to methylated DNA. It plays a role in regulating gene expression and is essential for normal brain development. Mutations in MeCP2 can cause Rett syndrome.

---

Rett syndrome

A rare genetic neurological disorder.

Rett syndrome primarily affects girls and is characterized by developmental regression, intellectual disability, and communication difficulties. It is caused by mutations in the MeCP2 gene.

---

MBD

Methyl-binding domain.

The MBD is a region within the MeCP2 protein that binds to methylated DNA. It plays a crucial role in regulating gene expression.