Salt bridge stability in monomeric proteins

Sandeep Kumar, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Here, we present the results of continuum electrostatic calculations on a dataset of 222 non-equivalent salt bridges derived from 36 non-homologous high-resolution monomeric protein crystal structures. Most of the salt bridges in our dataset are stabilizing, regardless of whether they are buried or exposed, isolated or networked, hydrogen bonded or nonhydrogen bonded. One-third of the salt bridges in our dataset are buried in the protein core, with the remainder exposed to the solvent. The difference in the dielectric properties of water versus the hydrophobic protein interior cost buried salt bridges large desolvation penalties. However, the electrostatic interactions both between the salt-bridging side-chains, and between the salt bridges and charges in their protein surroundings, are also stronger in the interior, due to the absence of solvent screening. Even large desolvation penalties for burying salt bridges are frequently more than compensated for, primarily by the electrostatic interactions between the salt-bridging side-chains. In networked salt bridges both types of electrostatic interactions, those between the salt-bridging side-chains, and those between the salt bridge and its protein environment, are of similar magnitudes. In particular, a major finding of this work is that salt bridge geometry is a critical factor in determining salt bridge stability. Salt bridges with favorable geometrical positioning of the interacting side-chain charged groups are likely to be stabilizing anywhere in the protein structure. We further find that most of the salt bridges are formed between residues that are relatively near each other in the sequence.

Original languageEnglish
Pages (from-to)1241-1255
Number of pages15
JournalJournal of Molecular Biology
Issue number5
StatePublished - 12 Nov 1999


FundersFunder number
Ministry of Science
National Institutes of HealthNO1-CO-56000
Academy of Leisure Sciences
United States-Israel Binational Science Foundation
Israel Science Foundation
Tel Aviv University
Institut National du Cancer


    • Electrostatics
    • Geometry
    • Hierarchical folding
    • Salt bridge
    • Stability


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