Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F25%3A10505830" target="_blank" >RIV/00216208:11160/25:10505830 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14310/25:00143527

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=.P51Hrel.Y" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=.P51Hrel.Y</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bpj.2025.09.037" target="_blank" >10.1016/j.bpj.2025.09.037</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops

Popis výsledku v původním jazyce

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 (&gt;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.

Název v anglickém jazyce

Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops

Popis výsledku anglicky

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 (&gt;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10301 - Atomic, molecular and chemical physics (physics of atoms and molecules including collision, interaction with radiation, magnetic resonances, Mössbauer effect)

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biophysical Journal

ISSN

0006-3495

e-ISSN

1542-0086

Svazek periodika

124

Číslo periodika v rámci svazku

21

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

3800-3810

Kód UT WoS článku

001616097400027

EID výsledku v databázi Scopus

2-s2.0-105020027602