Integration of Hydrogen-Deuterium Exchange Mass Spectrometry with Molecular Dynamics Simulations and Ensemble Reweighting Enables High Resolution Protein-Ligand Modeling

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F24%3A10485043" target="_blank" >RIV/00216208:11110/24:10485043 - isvavai.cz</a>

Result on the web

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

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/jasms.4c00202" target="_blank" >10.1021/jasms.4c00202</a>

Result language

angličtina

Original language name

Integration of Hydrogen-Deuterium Exchange Mass Spectrometry with Molecular Dynamics Simulations and Ensemble Reweighting Enables High Resolution Protein-Ligand Modeling

Original language description

Hydrogen-Deuterium exchange mass spectrometry&apos;s (HDX-MS) utility in identifying and characterizing protein-small molecule interaction sites has been established. The regions that are seen to be protected from exchange upon ligand binding indicate regions that may be interacting with the ligand, giving a qualitative understanding of the ligand binding pocket. However, quantitatively deriving an accurate high-resolution structure of the protein-ligand complex from the HDX-MS data remains a challenge, often limiting its use in applications such as small molecule drug design. Recent efforts have focused on the development of methods to quantitatively model Hydrogen-Deuterium exchange (HDX) data from computationally modeled structures to garner atomic level insights from peptide-level resolution HDX-MS. One such method, HDX ensemble reweighting (HDXer), employs maximum entropy reweighting of simulated HDX data to experimental HDX-MS to model structural ensembles. In this study, we implement and validate a workflow which quantitatively leverages HDX-MS data to accurately model protein-small molecule ligand interactions. To that end, we employ a strategy combining computational protein-ligand docking, molecular dynamics simulations, HDXer, and dimensional reduction and clustering approaches to extract high-resolution drug binding poses that most accurately conform with HDX-MS data. We apply this workflow to model the interaction of ERK2 and FosA with small molecule compounds and inhibitors they are known to bind. In five out of six of the protein-ligand pairs tested, the HDX derived protein-ligand complexes result in a ligand root-mean-square deviation (RMSD) within 2.5 &amp; Aring; of the known crystal structure ligand.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10600 - Biological sciences

Project

—

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2024

Confidentiality

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

Name of the periodical

Journal of the American Society for Mass Spectrometry

ISSN

1044-0305

e-ISSN

1879-1123

Volume of the periodical

35

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

2714-2728

UT code for WoS article

001310114500001

EID of the result in the Scopus database

2-s2.0-85205073257