Complex salt bridges in proteins: statistical analysis of structure and function.

Abstract

We developed an algorithm to analyze the distribution and geometry of simple and complex salt bridges in 94 proteins selected from the Protein Data Bank. In this study, the term "salt bridging" denotes both non-bonded and hydrogen-bonded paired electrostatic interactions between acidic carboxyl groups and basic amino groups in single or adjacent protein chains. We defined complex salt bridges as those joining more than two charged residues, including Asp, Glu, Lys and Arg, and excluding His. The survey related the following special features of complex salt bridges. (1) The abundance of complex salt bridges is high; one-third of all residues participating in salt-bridge formation were part of complex salt bridges. (2) The geometry of the interaction between acidic and basic residues is very similar in simple and complex salt bridges. Adding one residue to a simple interaction represents a minor change in the geometry but provides the molecule with a more complex interaction, a phenomenon that may explain the cooperative effect of salt bridges in proteins. Such moderate changes in salt-bridge networks can be generated stepwise and reversibly without trapping the protein in a local energetic minimum. (3) One important role of complex salt bridges is connecting protein subunits or joining two secondary structures to form quaternary structures, where they can connect as many as five secondary structure units. (4) Arginine serves as a key connector and/or a branching unit because its geometry allows three possible directions of interactions. The information gained from this study of complex salt bridges should enhance the understanding of protein structure.