Role of indirect readout in protein-DNA recognition assessed by a Bayesian approach

Yamasaki, Satoshi*; Fukui, Kazuhiko*; Kono, Hidetoshi; Shimizu, Kentaro*; Sarai, Akinori*; Terada, Toru*

Sequence-specific recognition of DNA by proteins plays a critical role in regulating gene expression. Accurate recognition is achieved by a combination of two different mechanisms. The first is direct readout, in which recognition is mediated by direct interactions between the protein and the DNA bases. The second is indirect readout, which is caused by the sequence-dependence of the conformation and deformability of the DNA structure. In our previous study, the contributions of indirect readout to binding affinity were evaluated for every tetrameric step in given protein-DNA complex structures. Using sequence-structure threading, potential energy differences between native and non-native tetrameric sequences for given tetrameric step conformation were compared. These potential energy functions were derived from the probability distribution function of its tetrameric step conformations calculated from trajectories of MD simulations of free DNAs which include all 136 types of tetramers. This gave good agreement with some experimental results, but shortage of structural sampling made the accurate estimation of distribution function difficult. In this work, we estimate the probability of occurrence of each tetrameric step sequence on given tetrameric step conformation using a Bayesian approach using the same structural dataset. We apply this approach to known protein-DNA complex structures, and assess the performance of predicting the sequence region where indirect readout makes important contribution to the binding affinity.