Capturing a dynamically interacting inhibitor by paramagnetic NMR spectroscopy

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00503801" target="_blank" >RIV/61388963:_____/19:00503801 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388980:_____/19:00503801 RIV/68378050:_____/19:00505253 RIV/00216208:11310/19:10393722

Výsledek na webu

<a href="https://pubs.rsc.org/en/content/articlelanding/2019/CP/C9CP00416E#!divAbstract" target="_blank" >https://pubs.rsc.org/en/content/articlelanding/2019/CP/C9CP00416E#!divAbstract</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c9cp00416e" target="_blank" >10.1039/c9cp00416e</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Capturing a dynamically interacting inhibitor by paramagnetic NMR spectroscopy

Popis výsledku v původním jazyce

Transient and fuzzy intermolecular interactions are fundamental to many biological processes. Despite their importance, they are notoriously challenging to characterize. Effects induced by paramagnetic ligands in the NMR spectra of interacting biomolecules provide an opportunity to amplify subtle manifestations of weak intermolecular interactions observed for diamagnetic ligands. Here, we present an approach to characterizing dynamic interactions between a partially flexible dimeric protein, HIV-1 protease, and a metallacarborane-based ligand, a system for which data obtained by standard NMR approaches do not enable detailed structural interpretation. We show that for the case where the experimental data are significantly averaged to values close to zero the standard fitting of pseudocontact shifts cannot provide reliable structural information. We based our approach on generating a large ensemble of full atomic models, for which the experimental data can be predicted, ensemble averaged and finally compared to the experiment. We demonstrate that a combination of paramagnetic NMR experiments, quantum chemical calculations, and molecular dynamics simulations offers a route towards structural characterization of dynamic protein-ligand complexes.

Název v anglickém jazyce

Capturing a dynamically interacting inhibitor by paramagnetic NMR spectroscopy

Popis výsledku anglicky

Transient and fuzzy intermolecular interactions are fundamental to many biological processes. Despite their importance, they are notoriously challenging to characterize. Effects induced by paramagnetic ligands in the NMR spectra of interacting biomolecules provide an opportunity to amplify subtle manifestations of weak intermolecular interactions observed for diamagnetic ligands. Here, we present an approach to characterizing dynamic interactions between a partially flexible dimeric protein, HIV-1 protease, and a metallacarborane-based ligand, a system for which data obtained by standard NMR approaches do not enable detailed structural interpretation. We show that for the case where the experimental data are significantly averaged to values close to zero the standard fitting of pseudocontact shifts cannot provide reliable structural information. We based our approach on generating a large ensemble of full atomic models, for which the experimental data can be predicted, ensemble averaged and finally compared to the experiment. We demonstrate that a combination of paramagnetic NMR experiments, quantum chemical calculations, and molecular dynamics simulations offers a route towards structural characterization of dynamic protein-ligand complexes.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

Physical Chemistry Chemical Physics

ISSN

1463-9076

e-ISSN

—

Svazek periodika

21

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

5661-5673

Kód UT WoS článku

000461722800028

EID výsledku v databázi Scopus

2-s2.0-85062591302