Geometric analysis and comparison of protein-DNA interfaces: Why is there no simple code for recognition?

Structural studies of protein-DNA complexes have shown that there are many distinct families of DNA-binding proteins, and have shown that there is no simple "code" describing side-chain/base interactions. How ever, systematic analysis and comparison of protein-DNA complexes has been complicated by t he diversity of observed contacts, the sheer number of complexes currently available and the absence of any consistent method of comparison that retai ns detailed structural information about the protein-DNA interface. To addr ess these problems, we have developed geometric methods for characterizing the local structural environment in which particular side-chain/base intera ctions are observed. In particular, we develop methods for analyzing and co mparing spatial relationships at the protein-DNA interface. Our method invo lves attaching local coordinate systems to the DNA bases and to the C-alpha atoms of the peptide backbone (these are relatively rigid structural units ). We use these tools to consider how the position and orientation of the p olypeptide backbone (with respect to the DNA) helps to determine what conta cts are possible at any given position in a protein-DNA complex. Here, we f ocus on base contacts that are made in the major groove, and we use spatial relationships in analyzing: (i) the observed patterns of side-chain/base i nteractions; (ii) observed helix docking orientations; (iii) family/subfami ly relationships among DNA-binding proteins; and (iv) broader questions abo ut evolution, altered specificity mutants and the limits for the design of new DNA-binding proteins. Our analysis, which highlights differences in spa tial relationships in different complexes and at different positions in a c omplex, helps explain why there is no simple, general code for protein-DNA recognition. (C) 2000 Academic Press.