Conformational changes in DNA‐binding proteins: Relationships with precomplex features and contributions to specificity and stability

Abstract

Both Proteins and DNA undergo conformational changes in order to form functional complexes and also to facilitate interactions with other molecules. These changes have direct implications for the stability and specificity of the complex, as well as the cooperativity of interactions between multiple entities. In this work, we have extensively analyzed conformational changes in DNA-binding proteins by superimposing DNA-bound and unbound pairs of protein structures in a curated database of 90 proteins. We manually examined each of these pairs, unified the authors' annotations, and summarized our observations by classifying conformational changes into six structural categories. We explored a relationship between conformational changes and functional classes, binding motifs, target specificity, biophysical features of unbound proteins, and stability of the complex. In addition, we have also investigated the degree to which the intrinsic flexibility can explain conformational changes in a subset of 52 proteins with high quality coordinate data. Our results indicate that conformational changes in DNA-binding proteins contribute significantly to both the stability of the complex and the specificity of targets recognized by them. We also conclude that most conformational changes occur in proteins interacting with specific DNA targets, even though unbound protein structures may have sufficient information to interact with DNA in a nonspecific manner.Proteins 2014; 82:841-857.

Statistical analysis of structural determinants for protein–DNA‐binding specificity

“…The plots based on the multiApoHolo set also show that the NS group has smaller structural variations in terms of median and MAD RMSD than those in the HS and MS groups (Figure 9E–F). These results suggest that the flexibility of DNA-binding proteins may contribute to their higher degree of binding specificity, which is consistent with previous findings using different metrics 59 .…”

Structural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode

“…In many other DNA binding proteins, DNAbinding dependent conformational changes in protein and/or DNA have been found to be important for DNA binding specificity and protein-DNA complex stability [44,45]. In line with this observation, the expanded conformational space of loop L1 in the BAX:AcK120 complex was accompanied by substantial structural changes that affected the quaternary structure of p53 tetramers and DNA structure, including DNA bending and unwinding, as well as helix deformation.…”

Protein interaction evolution from promiscuity to specificity with reduced flexibility in an increasingly complex network

“…The folding of monomer proteins is a highly dynamic process, that involves the equilibrium between several conformational states. Once an interaction partner comes close enough, some of these conformations will fold into the dimer conformation, which represents a lower -more favourable- energy state, and the more flexible the monomer is the larger the difference between free and bound conformations484950.…”