Sidechain interactions in parallel beta sheets: the energetics of cross-strand pairings

Background: Both backbone hydrogen bonding and interactions between sidecha ins stabilize beta sheets. Cross-strand interactions are the closest contac ts between the sidechains of a beta sheet. Here we investigate the energeti cs of cross-strand interactions using a variant of the B1 domain of immunog lobulin G (IgG) binding protein G (beta 1) as our model system. Results: Pairwise mutations of polar and nonpolar residues were made at a s olvent-exposed site between the two central parallel beta strands of beta 1 . Both stabilizing and destabilizing interactions were measured. The greate st stabilizations were observed for charge-charge interactions. Our experim ental study of sidechain interactions correlates with statistical preferenc es: residue pairs for which we measure stabilizing interaction energies occ ur together frequently, whereas destabilizing pairs are rarely observed tog ether. Conclusions: Sidechain interactions modulate the stability of beta sheets. We propose that cross-strand sidechain interactions specify correct strand register and ordering through the energetic benefit of optimally arranged p airings.