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

Result code in 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>
Result on the web
<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>

Result language
angličtina
Original language name
NMR-Derived Salt Bridges in Insulin Analogue: Resolving Artifactual Overbinding in Molecular Dynamics via Charge Scaling
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10403 - Physical chemistry

Project
<a href="/en/project/GA23-06755S" target="_blank" >GA23-06755S: Atomistic Understanding of Peptide Hormone Binding to Their Receptors and Mimetics Design via Advanced Computations and Experimental Verification</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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