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山崎 智*; 寺田 透*; 河野 秀俊; 清水 謙多郎*; 皿井 明倫*
Nucleic Acids Research, 40(17), p.e129_1 - e129_7, 2012/09
被引用回数：19 パーセンタイル：44.94(Biochemistry & Molecular Biology)Proteins recognize a specific DNA sequence not only through direct contact (direct readout) with base pairs but also through sequence-dependent conformation and/or flexibility of DNA (indirect readout). However, it is difficult to assess the contribution of indirect readout to the sequence specificity. What is needed is a straightforward method for quantifying its contributions to specificity. Using Bayesian statistics, we derived the probability of a particular sequence for a given DNA structure from the trajectories of molecular dynamics (MD) simulations of DNAs containing all possible tetramer sequences. Then, we quantified the specificity of indirect readout based on the information entropy associated with the probability. We tested this method with known structures of protein-DNA complexes. This method enabled us to correctly predict those regions where experiments suggested the involvement of indirect readout. The results also indicated new regions where the indirect readout mechanism makes major contributions to the recognition. The present method can be used to estimate the contribution of indirect readout without approximations to the distributions in the conformational ensembles of DNA, and would serve as a powerful tool to study the mechanism of protein-DNA recognition.
山崎 智*; 寺田 透*; 清水 謙多郎*; 河野 秀俊; 皿井 明倫*
Nucleic Acids Research, 37(20), p.e135_1 - e135_9, 2009/09
被引用回数：7 パーセンタイル：15.1(Biochemistry & Molecular Biology)Proteins recognize DNA sequences by 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 dependence of conformation and the deformability of the DNA structure on the sequence. Various energy functions have been proposed to evaluate the contribution of indirect readout to the free-energy changes in complex formations. We developed a new generalized energy function to estimate the dependence of the deformability of DNA on the sequence. This function was derived from molecular dynamics (MD) simulations previously conducted on B-DNA dodecamers, each of which had one possible tetramer sequence embedded at its center. By taking the logarithm of the probability distribution function (PDF) for the base-step parameters of the central base-pair step of the tetramer, its ability to distinguish the native sequence from random ones was superior to that with the previous method that approximated the energy function in harmonic form. From a comparison of the energy profiles calculated with these two methods, we found that the harmonic approximation caused significant errors in the conformational energies of the tetramers that adopted multiple stable conformations.
山崎 智*; 福井 一彦*; 河野 秀俊; 清水 謙多郎*; 皿井 明倫*; 寺田 透*
no journal, ,
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.
山崎 智*; 河野 秀俊; 清水 謙多郎*; 皿井 明倫*; 寺田 透*
no journal, ,
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 amino acids and DNA bases. The second is indirect readout, which is caused by the sequence-dependence of the conformation and deformability of the Drain the present study, we developed a new method for evaluating the contribution of indirect readout. This method uses the information entropy as a measure of the contribution. The entropy was calculated from the probability of DNA sequence given conformation, which was obtained by converting the probability of conformation given sequence using Bays'theorem. We used trajectories of MD simulations for free DNAs that had different tetramer sequences at the center of the sequences to calculate the probability distributions of the conformation. We found that the regions which are shown to be indirectly readout by experiment tend to have smaller information entropies. We therefore concluded that the information entropy is a good measure of the contribution of indirect readout in protein-DNA recognition.
山崎 智*; 寺田 透*; 河野 秀俊; 清水 謙多郎*; 皿井 明倫*
no journal, ,
Sequence-specific recognition of DNA by proteins plays a critical role in regulating gene expression. The accurate recognition of target sequences in the genome can be achieved by a combination of two different mechanisms: the direct readout through the direct interactions between protein and DNA bases; and the indirect readout through the sequence-dependent conformation and/or deformability of DNA structure. While the specificity of direct readout has been well characterized, it is rather difficult to assess the contribution of indirect readout to the specificity. In order to quantify the specificity of indirect readout, we have developed a new method. First, we used Bayesian statistics to derive the probability of a particular sequence for a given DNA structure using ensembles obtained by molecular dynamics (MD) simulations of DNAs containing all 136 unique tetramer sequences. Secondly, we used the information entropy to quantify the specificity of indirect readout. We applied this method to protein-DNA complexes of known structures to examine its validity. We could correctly predict those regions where experiments suggested the involvement of indirect readout, and could indicate new regions where the indirect readout mechanism can make major contributions to the recognition. The present probability/entropy-based approach has advantage over the previous energy-based approach in that the trajectories of MD simulation can be directly converted into the probability of sequence and the specificity of indirect readout without any approximation to the distributions in the conformational ensembles of DNA, and would serve as a powerful tool to study the mechanism of protein-DNA recognition.
