Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops
| Authors | |
|---|---|
| Year of publication | 2025 |
| Type | Article in Periodical |
| Magazine / Source | BIOPHYSICAL JOURNAL |
| MU Faculty or unit | |
| Citation | |
| web | https://www.cell.com/biophysj/abstract/S0006-3495(25)00617-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0006349525006174%3Fshowall%3Dtrue |
| Doi | https://doi.org/10.1016/j.bpj.2025.09.037 |
| Keywords | PHOSPHORYLATION; TAU-PROTEIN |
| Description | Within the disordered tangles of Tau is a proline-rich region, which is selectively targeted by the SH3 domain of BIN1, a known genetic factor for Alzheimer disease, and may hold the key to understanding the disorder and treatment strategies. Hyperphosphorylation of Tau is known to disrupt complex formation, providing researchers with excellent preventative or remediative targets. This work compiles an extensive (>60 mu s) collection of all-atomistic molecular dynamics simulations of the Tau(210-240) fragment, representing the majority of the P2 subdomain of the proline-rich region, benchmarking various force fields, phosphorylations, and modifications against experimental NMR chemical shifts and spin-spin coupling for comparison. Additionally, several simulations of the binding complex were analyzed for their binding energies by MMGBSA calculations and computational alanine scanning to pinpoint the exact residues involved and the disruptions caused by the phosphate group. We noted that the additional charges decrease salt bridges formed by positive residues in Tau, particularly on R221, and negative residues in BIN1 by up to 32%, and a strong preference in Tau, particularly in the latter half, for contact toward the distal and n-Src loops instead of residues in the RT-Src loop. |
| Related projects: |