Evaluatingthe Strength of Salt Bridges: A Comparisonof Current Biomolecular Force Fields.

Recent advances in computer hardwareand software have made rigorousevaluation of current biomolecular force fields using microsecond-scalesimulations possible. Force fields differ in their treatment of electrostaticinteractions, including the formation of salt bridges in proteins.Here we conducted an extensive evaluation of salt bridge interactionsin the latest AMBER, CHARMM, and OPLS force fields, using microsecond-scalemolecular dynamics simulations of amino acid analogues in explicitsolvent. We focused on salt bridges between three different pairsof oppositely charged amino acids: Arg/Asp, Lys/Asp, and His(+)/Asp.Our results reveal considerable variability in the predicted KAvalues of the salt bridges for these forcefields, as well as differences from experimental data: almost allof the force fields overestimate the strengths of the salt bridges.When amino acids are represented by side-chain analogues, the AMBERff03 force field overestimates the KAvaluesthe least, while for complete amino acids, the AMBER ff13α forcefield yields the lowest KAvalue, mostlikely caused by an altered balance of side-chain/side-chain and side-chain/backbonecontacts. These findings confirm the notion that the implicit incorporationof solvent polarization improves the accuracy of modeling salt bridgeinteractions. [ABSTRACT FROM AUTHOR]