scholarly journals Dynamic and Structural Modeling of the Specificity in Protein-DNA Interactions Guided by Binding Assay and Structure Data

2018 ◽  
Author(s):  
Cheng Tan ◽  
Shoji Takada

ABSTRACTHow transcription factors (TFs) recognize their DNA sequences is often investigated complementarily by high-throughput protein binding assays and by structural biology experiments. The former quantifies the specificity of TF binding sites for numerous DNA sequences, often represented as the position-weight-matrix (PWM). The latter provides mechanistic insights into the interactions via the protein-DNA complex structures. However, these two types of data are not readily integrated. Here, we propose and test a new modeling method that incorporates the PWM with complex structure data. Based on pre-tuned coarse-grained models for proteins and DNAs, we model the specific protein-DNA interactions, PWMcos, in terms of an orientation-dependent potential function, which enables us to perform molecular dynamics simulations at unprecedentedly large scales. We show that the PWMcos model reproduces subtle specificity in the protein-DNA recognition. During the target search in genomic sequences, TF moves on highly rugged landscapes and occasionally flips on DNA depending on the sequence. The TATA-binding protein exhibits two remarkably distinct binding modes, of which frequencies differ between TATA-containing and TATA-less promoters. The PWMcos is general and can be applied to any protein-DNA interactions given their PWMs and complex structure data are available.

2021 ◽  
Author(s):  
Antonio Bauza ◽  
Alberto Perez

Herein we present MELD-DNA, a novel computational approach to address the problem of protein-DNA structure prediction. This method addresses well-known issues hampering current computational approaches to bridge the gap between structural and sequence knowledge, such as large conformational changes in DNA and highly charged electrostatic interaction during binding. MELD- DNA is able to: i) sample multiple binding modes, ii) identify the preferred binding mode from the ensembles, and iii) provide qualitative binding preferences between DNA sequences. We expect the results presented herein will have impact in the field of biophysics (through new software development), structural biology (by complementing DNA structural databases) and supramolecular chemistry (by bringing new insights into protein-DNA interactions).


Soft Matter ◽  
2019 ◽  
Vol 15 (26) ◽  
pp. 5255-5263 ◽  
Author(s):  
Jaeoh Shin ◽  
Anatoly B. Kolomeisky

DNA looping is facilitated by non-specific protein–DNA interactions.


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