RESEARCH: CANCER
FOLDING PROJECT #12431 PROFILE

This project studies how tiny proteins fold into their shapes and how changes in their code affect this folding. Using powerful computer simulations, they're trying to understand how these small changes can lead to bigger problems, like the neurological disorder 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.

---

protein

A large biomolecule composed of amino acids.

Proteins are essential molecules found in all living organisms. They perform a wide range of functions, including catalyzing biochemical reactions, transporting molecules, and providing structural support.

---

fold

The three-dimensional shape of a protein.

A protein's fold is its unique three-dimensional structure, which is crucial for its function. The folding process is complex and influenced by various factors.

---

mutation

A permanent change in the DNA sequence.

Mutations are alterations in the genetic code that can lead to changes in protein structure and function. They can be beneficial, harmful, or have no effect.

---

transcription factor

A protein that binds to DNA and regulates gene expression.

Transcription factors play a vital role in controlling which genes are turned on or off. They bind to specific DNA sequences and influence the rate of transcription.

---

FOXO1

Forkhead box O1 transcription factor

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

---

MeCP2

Methyl-CpG binding protein 2

MeCP2 is a protein that binds to methylated DNA and regulates gene expression. Mutations in the MeCP2 gene can cause Rett syndrome.

---

Rett syndrome

A rare genetic disorder that primarily affects females.

Rett syndrome is a neurodevelopmental disorder characterized by progressive loss of motor and language skills. It is caused by mutations in the MeCP2 gene.