The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids

The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer’s disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of human (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in modulating the dynamics of the Ig-like domain and altering the accessibility of ..., , # The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids

Dataset DOI: [10.5061/dryad.0000000gn](10.5061/dryad.0000000gn)

## Description of the data and file structure

MD trajectories, structure files, and analysis files (RMSD, RMSF) as outlined in the associated eLife paper. [https://doi.org/10.7554/eLife.102269.2](https://doi.org/10.7554/eLife.102269.2)

### Files and variables

#### File: eLife_Data_Availability.zip

**Description:** This directory contains molecular dynamics (MD) trajectories, structure files, and analysis outputs (RMSD and RMSF) corresponding to the simulations described in the associated eLife paper.

**Folder Structure**

The top-level directory contains two main folders:

* `WT/` — Wild-type (s)TREM2 simulations
* `R47H/` — R47H mutant (s)TREM2 simulations

Within each of these, subdirectories are organized by the simulated system. For example:

* `PSIG/` — Simulations of the Ig-like domain of TREM2 in the presence of pho...,