Dataset Information

Tunable order-disorder continuum in protein-DNA interactions.

ABSTRACT: DNA-binding protein domains (DBDs) sample diverse conformations in equilibrium facilitating the search and recognition of specific sites on DNA over millions of energetically degenerate competing sites. We hypothesize that DBDs have co-evolved to sense and exploit the strong electric potential from the array of negatively charged phosphate groups on DNA. We test our hypothesis by employing the intrinsically disordered DBD of cytidine repressor (CytR) as a model system. CytR displays a graded increase in structure, stability and folding rate on increasing the osmolarity of the solution that mimics the non-specific screening by DNA phosphates. Electrostatic calculations and an Ising-like statistical mechanical model predict that CytR exhibits features of an electric potential sensor modulating its dimensions and landscape in a unique distance-dependent manner, while DNA plays the role of a non-specific macromolecular chaperone. Accordingly, CytR binds its natural half-site faster than the diffusion-controlled limit and even random DNA conforming to an electrostatic-steering binding mechanism. Our work unravels for the first time the synergistic features of a natural electrostatic potential sensor, a novel binding mechanism driven by electrostatic frustration and disorder, and the role of DNA in promoting distance-dependent protein structural transitions critical for switching between specific and non-specific DNA-binding modes.

SUBMITTER: Munshi S

PROVIDER: S-EPMC6158747 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Tunable order-disorder continuum in protein-DNA interactions.

Munshi Sneha S Gopi Soundhararajan S Asampille Gitanjali G Subramanian Sandhyaa S Campos Luis A LA Atreya Hanudatta S HS Naganathan Athi N AN

Nucleic acids research 20180901 17

DNA-binding protein domains (DBDs) sample diverse conformations in equilibrium facilitating the search and recognition of specific sites on DNA over millions of energetically degenerate competing sites. We hypothesize that DBDs have co-evolved to sense and exploit the strong electric potential from the array of negatively charged phosphate groups on DNA. We test our hypothesis by employing the intrinsically disordered DBD of cytidine repressor (CytR) as a model system. CytR displays a graded inc ...[more]

PMID: 30107436

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Project description:BackgroundMore and more disordered regions have been discovered in protein sequences, and many of them are found to be functionally significant. Previous studies reveal that disordered regions of a protein can be predicted by its primary structure, the amino acid sequence. One observation that has been widely accepted is that ordered regions usually have compositional bias toward hydrophobic amino acids, and disordered regions are toward charged amino acids. Recent studies further show that employing evolutionary information such as position specific scoring matrices (PSSMs) improves the prediction accuracy of protein disorder. As more and more machine learning techniques have been introduced to protein disorder detection, extracting more useful features with biological insights attracts more attention.ResultsThis paper first studies the effect of a condensed position specific scoring matrix with respect to physicochemical properties (PSSMP) on the prediction accuracy, where the PSSMP is derived by merging several amino acid columns of a PSSM belonging to a certain property into a single column. Next, we decompose each conventional physicochemical property of amino acids into two disjoint groups which have a propensity for order and disorder respectively, and show by experiments that some of the new properties perform better than their parent properties in predicting protein disorder. In order to get an effective and compact feature set on this problem, we propose a hybrid feature selection method that inherits the efficiency of uni-variant analysis and the effectiveness of the stepwise feature selection that explores combinations of multiple features. The experimental results show that the selected feature set improves the performance of a classifier built with Radial Basis Function Networks (RBFN) in comparison with the feature set constructed with PSSMs or PSSMPs that adopt simply the conventional physicochemical properties.ConclusionDistinguishing disordered regions from ordered regions in protein sequences facilitates the exploration of protein structures and functions. Results based on independent testing data reveal that the proposed predicting model DisPSSMP performs the best among several of the existing packages doing similar tasks, without either under-predicting or over-predicting the disordered regions. Furthermore, the selected properties are demonstrated to be useful in finding discriminating patterns for order/disorder classification.

Dataset Information

Tunable order-disorder continuum in protein-DNA interactions.

Publications

Tunable order-disorder continuum in protein-DNA interactions.

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