Effects of salt bridges on protein structure and design

Abstract

Theoretical calculations (Hendsch ZS & Tidor B, 1994, Protein Sci 3:211-226) and experiments (Waldburger CD et al., 1995, Nut Struct Biol 2:122-128;Wimley WC et al., 1996, Proc Natl Acud Sci USA 93:2985-2990) suggest that hydrophobic interactions are more stabilizing than salt bridges in protein folding. The lack of apparent stability benefit for many salt bridges requires an alternative explanation for their occurrence within proteins. To examine the effect of salt bridges on protein structure and stability in more detail, we have developed an energy function for simple cubic lattice polymers based on continuum electrostatic calculations of a representative selection of salt bridges found in known protein crystal structures. There are only three types of residues in the model, with charges of -1, 0, or + 1. We have exhaustively enumerated conformational space and significant regions of sequence space for three-dimensional cubic lattice polymers of length 16. The results demonstrate that, while the more highly charged sequences are less stable, the loss of stability is accompanied by a substantial reduction in the degeneracy of the lowest-energy state. Moreover, the reduction in degeneracy is greater due to charges that pair than for lone charges that remain relatively exposed to solvent. We have also explored and illustrated the use of ion-pairing strategies for rational structural design using model lattice studies.

An Integrated Structural and Computational Study of the Thermostability of Two Thioredoxin Mutants fromAlicyclobacillus acidocaldarius

“…Sequence and structural comparisons between functionally homologous proteins from mesophilic and thermophilic organisms have pointed out that high thermal stability is usually related to multiple factors (8,11,16,17,19,20,25,37,39,41,42,(45)(46)(47)(48). Recently, a series of findings have suggested that thermostability can be also achieved by single ad hoc mutations, possibly allowing the formation of ion pairs or ion networks (26, 44) and/or optimization of long-range coulombic interactions on the protein surface (15,23,36,40).…”

Electrostatic interactions in the GCN4 leucine zipper: Substantial contributions arise from intramolecular interactions enhanced on binding

“…One suggestion from the work is that the replacement of salt bridges with hydrophobic groups of similar size and shape could lead to more stable proteins. A further suggestion advanced is that compensated electrostatic interactions, even if destabilizing, could enhance specificity by dramatically disfavoring arrangements in which polar and charged groups are buried but not compensated~Hendsch & Tidor, 1994;Sindelar et al, 1998!. In an experimental study involving combinatorial mutagenesis of a salt bridge triad in Arc repressor, Waldburger et al~1995! found that simultaneous hydrophobic substitutions for all three members of the salt bridge triad produced stability enhancements in the range of 1-2 teins, respectively, Wimley et al~1996!…”

Counterion effects in protein nanoparticle electrostatic binding: A theoretical study

“…It only maintains the specific folding of protein, and its functional interactions [33,34]. A simple form of the electrostatic energy, E ES , is given by the distance-attenuated Coulomb interaction term [16],…”