PROJECT #18451 RESEARCH FOR CANCER
FOLDING PERFORMANCE PROFILE

PROJECT SUMMARY

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..

PROJECT INFO

Manager(s): Dylan Novack

Institution: Temple University

Project URL: http://voelzlab.org

PROJECT WORK UNIT SUMMARY

Atoms: 40,908

Core: 0x22

Status: Public