The energetics of structural change in maltose-binding protein.

H igh-resolution structures of proteins and their complexes are now appearing in the Research Collaboratory for Structural Bioinformatics (RCSB) database at a tremendous rate. When analyzing the structures of proteins, it is often tempting to try to extract energetic contributions to stability or binding interactions. However, as many experiments have shown, some specific interactions that look important are not, whereas others that seem minor turn out to have key roles. In evaluating detailed structures, particularly to understand subtle structural differences in mutants, one always wants the highestresolution structures available, and most of these come from crystallography. However, crystallography suffers from the ‘‘tyranny of the lattice’’ (the ability of the forces that stabilize the crystal lattice to alter the conformation of the molecules making up the crystal). Although this term has been used most often for nucleic acids (see ref. 1 for a discussion of the issues), the idea applies to proteins as well; there are many examples in which the structure of a loop is different in different crystal forms, leaving ambiguity as to the ‘‘true’’ conformation in solution. The relative positions of domains in multidomain proteins also can be affected by intermolecular interactions. In this issue of PNAS, an NMR approach for determining relative domain orientation in solution has been applied to a series of mutants of a two-domain protein (2). By combining this approach with energetic information derived from careful protein stability measurements, it became possible to provide remarkably detailed insight into the energetic cost of induced structural change and how it couples to ligand binding.