NMR-Derived Salt Bridges in Insulin Analogue: Resolving Artifactual Overbinding in Molecular Dynamics via Charge Scaling

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00637626" target="_blank" >RIV/61388963:_____/25:00637626 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jpclett.5c01786" target="_blank" >https://doi.org/10.1021/acs.jpclett.5c01786</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jpclett.5c01786" target="_blank" >10.1021/acs.jpclett.5c01786</a>

Jazyk výsledku

angličtina

Název v původním jazyce

NMR-Derived Salt Bridges in Insulin Analogue: Resolving Artifactual Overbinding in Molecular Dynamics via Charge Scaling

Popis výsledku v původním jazyce

Salt bridges are ionic interactions that are of great importance in protein recognition. However, their structural description using X-ray crystallography or NMR may be inconclusive. Classical molecular dynamics (MD) used for the interpretation neglects electronic polarization, which results in artifactual overbinding. Here, we resolve the problem via charge scaling, which accounts for electronic polarization in a mean-field way. We study three salt bridges in insulin analogue. New NMR ensembles are generated via NOE-restrained MD using ff19SB and CHARMM36m force fields and the scaled-charge prosECCo75. Tens of mu s of unrestrained MD show in a statistically converged manner that ff19SB induces a non-native salt bridge. This behavior is quantified via umbrella sampling of salt bridge dissociation, which indicates a rather high strength of up to 4 and 5 kcal mol-1 for CHARMM36m and ff19SB, respectively. In contrast, prosECCo75 gives a biologically reasonable dissociation barrier of 1 kcal mol-1. Our results indicate that a physically justified description of charge-charge interactions within a nonpolarizable MD framework reliably describes aqueous biomolecular systems.

Název v anglickém jazyce

NMR-Derived Salt Bridges in Insulin Analogue: Resolving Artifactual Overbinding in Molecular Dynamics via Charge Scaling

Popis výsledku anglicky

Salt bridges are ionic interactions that are of great importance in protein recognition. However, their structural description using X-ray crystallography or NMR may be inconclusive. Classical molecular dynamics (MD) used for the interpretation neglects electronic polarization, which results in artifactual overbinding. Here, we resolve the problem via charge scaling, which accounts for electronic polarization in a mean-field way. We study three salt bridges in insulin analogue. New NMR ensembles are generated via NOE-restrained MD using ff19SB and CHARMM36m force fields and the scaled-charge prosECCo75. Tens of mu s of unrestrained MD show in a statistically converged manner that ff19SB induces a non-native salt bridge. This behavior is quantified via umbrella sampling of salt bridge dissociation, which indicates a rather high strength of up to 4 and 5 kcal mol-1 for CHARMM36m and ff19SB, respectively. In contrast, prosECCo75 gives a biologically reasonable dissociation barrier of 1 kcal mol-1. Our results indicate that a physically justified description of charge-charge interactions within a nonpolarizable MD framework reliably describes aqueous biomolecular systems.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

<a href="/cs/project/GA23-06755S" target="_blank" >GA23-06755S: Porozumění vazbě peptidový‎ch hormonů k jejich receptorům na atomární úrovni a návrh mimetik pomocí pokročilých vý‎počtů a experimentálního ověření</a><br>

Návaznosti

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

Journal of Physical Chemistry Letters

ISSN

1948-7185

e-ISSN

—

Svazek periodika

16

Číslo periodika v rámci svazku

29

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

7

Strana od-do

7436-7442

Kód UT WoS článku

001530048400001

EID výsledku v databázi Scopus

2-s2.0-105012420302