Role of Shape Deformation of DNA-Binding Sites in Regulating the Efficiency and Specificity in Their Recognition by DNA-Binding Proteins

Accurate transcription of genetic information is crucial, involving precise recognition of the binding motifs by DNA-binding proteins. While some proteins rely on short-range hydrophobic and hydrogen bonding interactions at binding sites, others employ a DNA shape readout mechanism for specific recognition. In this mechanism, variations in DNA shape at the binding motif resulted from either inherent flexibility or binding of proteins at adjacent sites are sensed and capitalized by the searching proteins to locate them specifically. Through extensive computer simulations, we investigate both scenarios to uncover the underlying mechanism and origin of specificity in the DNA shape readout mechanism. Our findings reveal that deformation in shape at the binding motif creates an entropy funnel, allowing information about altered shapes to manifest as fluctuations in minor groove widths. This signal enhances the efficiency of nonspecific search of nearby proteins by directing their movement toward the binding site, primarily driven by a gain in entropy. We propose this as a generic mechanism for DNA shape readout, where specificity arises from the alignment between the molecular frustration of the searching protein and the ruggedness of the entropic funnel governed by molecular features of the protein and arrangement of the DNA bases at the binding site, respectively.