RESEARCH: ALZHEIMERS
FOLDING PROJECT #18256 PROFILE

Alzheimer's disease is caused by clumps of a protein called tau. Studying tau is hard because it doesn't have a fixed shape. This project uses computer simulations to figure out the best way to model tau, which will help us understand Alzheimer's better.

Note: This TLDR is a simplication and may not be 100% accurate.

Alzheimer's disease is a significant cause of death and memory loss and there are no effective treatments to halt or reverse disease progression.

One of the late hallmarks and primary biomarkers of Alzheimer's disease is the presence of neurofibrillary tangles, intracellular aggregates of the tau protein.

When behaving properly, tau interacts with microtubules- a critical portion of the cytoskeleton of cells- to help regulate their growth and stability.

However, tau misbehavior and aggregation is also closely linked to Alzheimer's disease among many other neurodegenerative diseases. Studying tau experimentally has been difficult as it is an Intrinsically Disordered Protein (IDP).

As such, traditional structural biology approaches are unable to capture the conformational states of tau in atomistic detail.

Recently, our collaborators have utilized single molecule FRET experiments to experimentally characterize tau by measuring the pairwise distance between different regions.

While simulations of tau could provide atomistic detail of the tau conformational ensemble, historically simulations of IDPs have been challenging as force fields (the parameters which govern the underlying physics of a simulation) and their accompyning models of waters have favored well-folded proteins.

In this project series we embark on an effort to characterize which force field and water models most accurately recapitulate tau experimental results.

We believe these findings will be broadly applicable to all researchers studying intrinsically disordered proteins, and aspire to keep performing these benchmarking simulations as new force field and waters are released.

We also expect these simulations to yield useful information about the tau conformational ensemble. N.B.

because tau is an intrinsically disordered protein, it can fully unfold and refold quite rapidly.

To ensure the protein remains in water the entire simulation, we have included a large number of waters in the system.

As a result these simulations are a good deal more RAM intensive than prior FAH simulations.

Accordingly, we have implemented a minimum system memory requirement of 8000 MiB to run these simulations.

p18251 - amber99sb-disp with tip4pd water p18255- amber14sb with tip3p water p18256- amber03 with tip3p water p18257- amber19sb with opc water p18258- amber19sb with opc3 water p18259 - amber19sb with opc3 pol water p18260- amber99sb-star-ILDN with tip4pd water p18261- charmm36m with tip3p water.

---

Alzheimer's disease

A progressive neurodegenerative disorder characterized by memory loss and cognitive decline.

Alzheimer's disease is a serious brain disorder that causes problems with thinking, memory, and behavior. It is the most common cause of dementia, a condition that affects many aspects of life.

---

neurofibrillary tangles

Abnormal accumulations of tau protein inside nerve cells.

Neurofibrillary tangles are clumps of twisted fibers found in the brains of people with Alzheimer's disease. They disrupt normal cell function and contribute to brain damage.

---

tau protein

A protein involved in stabilizing microtubules.

Tau is a protein that helps maintain the structure of nerve cells. In Alzheimer's disease, tau becomes abnormally twisted and clumps together, forming neurofibrillary tangles.

---

microtubules

Hollow protein tubes that help maintain cell shape and transport materials.

Microtubules are important structural components of cells. They provide support, facilitate movement, and play a role in intracellular transport.

---

Intrinsically Disordered Protein (IDP)

A protein that lacks a fixed three-dimensional structure.

Intrinsically disordered proteins (IDPs) are unique because they don't have a stable shape. This allows them to be flexible and interact with many different molecules.

---

force fields

Parameters that govern the interactions between atoms in a molecular simulation.

Force fields are mathematical models used to simulate the behavior of molecules. They help researchers understand how proteins fold and interact with each other.

---

simulations

Computer models used to predict the behavior of biological systems.

Simulations are powerful tools that allow researchers to study complex biological processes in a virtual environment.

---

FRET

Förster Resonance Energy Transfer

FRET is a technique used to study the interactions between molecules by measuring the transfer of energy between fluorescent probes.