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 μs 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.

• Publication type
• Journal Article MeSH

Cation-π interactions involving the tetramethylammonium motif are prevalent in biological systems, playing crucial roles in membrane protein function, DNA expression regulation, and protein folding. However, accurately modeling cation-π interactions where electronic polarization plays a critical role is computationally challenging, especially in large biomolecular systems. This study implements a physically justified electronic continuum correction (ECC) to the CHARMM36 force field, scaling ionic charges by a factor of 0.75 to effectively account for electronic polarization without additional computational overhead. This approach, while not specifically designed for cation-π interactions, is shown here to significantly improve predictions of the structure of an aqueous tetramethylammonium-pyridine complex as compared to neutron diffraction data. This result, together with computational predictions for the structure of the aqueous tetramethylammonium-phenol complex, underscores the potential of ECC as a versatile method to improve the description of cation-π interactions in biomolecular simulations.

• MeSH
• Cations chemistry   MeSH
• Quaternary Ammonium Compounds * chemistry   MeSH
• Neutron Diffraction MeSH
• Molecular Dynamics Simulation * MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cations MeSH
• Quaternary Ammonium Compounds * MeSH
• tetramethylammonium MeSH Browser