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Chargedamino acids are the most common on surfaces of proteinsand understanding the interactions between these charged amino acids,salt bridging, is crucial for understanding protein–proteininteractions. Previous simulations have been limited to implicit solventor fixed binding geometry due to the sampling required for convergedfree energies. Using well-tempered metadynamics, we have calculatedsalt bridge free energy surfaces in water and confirmed the resultswith NMR experiments. The simulations give binding free energies,quantitative ranking of salt bridging strength, and insights intothe hydration of the salt bridges. The arginine–aspartate saltbridge was found to be the weakest and arginine-glutamate the strongest,showing that arginine can discriminate between aspartate and glutamate,whereas the salt bridges with lysine are indistinguishable in theirfree energy. The salt bridging hydration is found to be complementaryto salt bridge orientation with arginine having specific orientations. [ABSTRACT FROM AUTHOR]