Disruption and Formation of Surface Salt Bridges Are Coupled to DNA Binding by the Integration Host Factor: A Computational Analysis

Ma, Liang; Sundlass, Nadia K.; Raines, Ronald T.; Cui, Qiang

doi:10.1021/bi101096k

Cited by 12 publications

(12 citation statements)

References 47 publications

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“…A previously performed molecular dynamics study on E. coli IHF by Ma at al. showed K15, R21, R77 and K97 of IHFα and K69 of IHFβ have a high probability of forming salt bridges in native condition, but in DNA-bound structure (PDB: 1IHF) the salt bridges were missing (Ma et al, 2010). Due to IHFs enrichment of both positive and negatively charged residues in the BDR compared to HU, its salt-bridge making capacity is also much higher, as we observed from comparative structural analysis.…”

Section: Salt Bridges Drive Specificity By Constraining Flexibility Imentioning

confidence: 52%

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Phylogenetic and structural analyses reveal the determinants of DNA binding specificities of nucleoid-associated proteins HU and IHF

Dey

Nagaraja

Ramakumar

2016

Preprint

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Nucleoid-associated proteins (NAPs) are chromosome-organizing factors, which affect the transcriptional landscape of a bacterial cell. HU is an NAP, which binds to DNA with a broad specificity while homologous IHF (Integration Host Factor), binds DNA with moderately higher specificity. Specificity and differential binding affinity of HU/IHF proteins towards their target binding sites play a crucial role in their regulatory dynamics. Decades of biochemical and genomic studies have been carried out for HU and IHF like proteins. Yet, questions related to their DNA binding specificity, and differential ability to bend DNA thus affecting the binding site length remained unanswered. In addition, the problem has not been investigated from an evolutionary perspective. Our phylogenetic analysis revealed three major clades belonging to HU, IHFα and IHFβ like proteins with reference to E. coli. We carried out a comparative analysis of three-dimensional structures of HU/IHF proteins to gain insight into the structural basis of clade division. The present study revealed three major features which contribute to differential DNA binding specificity of HU/IHF proteins, I) conformational restriction of DNA binding residues due to salt-bridge formation II) the enrichment of alanine in the DNA binding site increasing conformational space of flexible side chains in its vicinity and III) nature of DNA binding residue (Arg to Lys bias in different clades) which interacts differentially to DNA bases. Differences in the dimer stabilization strategies between HU and IHF were also observed. Our analysis reveals a comprehensive evolutionary picture, which rationalizes the origin of multi-specificity of HU/IHF proteins using sequence and structure-based determinants, which could also be applied to understand differences in binding specificities of other nucleic acid binding proteins.

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Section: Salt Bridges Drive Specificity By Constraining Flexibility Imentioning

confidence: 52%

“…Earlier studies have hinted at the importance of salt bridge rearrangements at the DNA binding interface (Ma et al, 2010). A previously performed molecular dynamics study on E. coli IHF by Ma at al.…”

Section: Salt Bridges Drive Specificity By Constraining Flexibility Imentioning

confidence: 99%

Phylogenetic and structural analyses reveal the determinants of DNA binding specificities of nucleoid-associated proteins HU and IHF

Dey

Nagaraja

Ramakumar

2016

Preprint

View full text Add to dashboard Cite

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“…On the other hand, the freedom of most amino acid side chains of the binding pocket will be reduced. A similar model has been proposed by Holbrook et al (2001) and analyzed by Ma et al (2011) to explain the thermodynamics of a protein-DNA binding.…”

Section: Discussionmentioning

confidence: 73%

Salt bridge exchange binding mechanism between streptavidin and its DNA aptamer – thermodynamics and spectroscopic evidences

Kuo

Lee

Tsai

et al. 2013

J of Molecular Recognition

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Protein-nucleic acids binding driven by electrostatic interactions typically are characterized by the release of counter ions, and the salt-inhibited binding association constant (K(a)) and the magnitude of exothermic binding enthalpy (ΔH). Here, we report a non-classical thermodynamics of streptavidin (SA)-aptamer binding in NaCl (140-350 mM) solutions near room temperatures (23-27 °C). By using isothermal titration calorimetry (ITC) and circular dichroism (CD)/fluorescence spectroscopy, we found that the binding was enthalpy driven with a large entropy cost (ΔH -20.58 kcal mol(-1), TΔS -10.99 kcal mol(-1), and K(a) 1.08 × 10(7) M(-1) at 140 mM NaCl 25 °C). With the raise of salt concentrations, the ΔH became more exothermic, yet the K(a) was almost unchanged (ΔH -26.29 kcal mol(-1) and K(a) 1.50 × 10(7) M(-1) at 350 mM NaCl 25 °C). The data suggest that no counter Na(+) was released in the binding. Spectroscopy data suggest that the binding, with a stoichiometry of 2, was accompanied with substantial conformational changes on SA, and the changes were insensitive to the variation of salt concentrations. To account for the non-classical results, we propose a salt bridge exchange model. The intramolecular binding-site salt bridge(s) of the free SA and the charged phosphate group of aptamers re-organize to form the binding complex by forming a new intermolecular salt bridge(s). The salt bridge exchange binding process requires minimum amount of counter ions releasing but dehydration of the contacting surface of SA and the aptamer. The energy required for dehydration is reduced in the case of binding solution with higher salt concentration and account for the higher binding exothermic mainly.

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“…In the case of ABH2, the long loop region (Asp201‐Val211) does not form many contacts with the DNA in the crystal structure; upon structural relaxation of the loop in the MD simulation, however, interactions form, a result in line with the proposed role of this loop region in binding with the dsDNA . These examples highlight the value of combining MD simulations and structural studies for better understanding protein‐DNA interactions and their functional implications, especially for systems in which the protein/DNA may undergo significant changes from their conformations in isolation . Finally, it is worth noting that, despite substantial structural distortions in the DNA, the local conformations of most normal base‐pairs are well maintained during the MD simulations of AlkB‐dsDNA and ABH2‐dsDNA.…”

Section: Discussionmentioning

confidence: 89%

A simple but effective modeling strategy for structural properties of non‐heme Fe(II) sites in proteins: Test of force field models and application to proteins in the AlkB family

2013

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To facilitate computational study of proteins in the AlkB family and related a-ketoglutarate/Fe(II)-dependent dioxygenases, we have tested a simple modeling strategy for the non-heme Fe(II) site in which the iron is represented by a simple 12 point charge with Lennard-Jones parameters. Calculations for an AlkB active site model in the gas phase and $150 ns molecular dynamics (MD) simulations for two enzyme-dsDNA complexes (E. coli AlkB-dsDNA and ABH2-dsDNA) suggest that this simple modeling strategy provides a satisfactory description of structural properties of the Fe(II) site in AlkB enzymes, provided that care is exercised to control the binding mode of carboxylate (Asp) to the iron. MD simulations using the model for AlkB-dsDNA and ABH2-dsDNA systems find that although the structural features for the latter are overall in good agreement with the crystal structure, the dsDNA, and AlkB-dsDNA interface undergo substantial changes during the MD simulations from the crystal structure. Even for ABH2, new interactions form between a long loop region and dsDNA upon structural relaxation of the loop, supporting the role of this loop in DNA binding despite the lack of interactions between them in the crystal structure. Analysis of DNA backbone torsional distributions helps identify regions that adopt strained conformations. Collectively, the results highlight that crystal packing may have a significant impact on the structure of protein-DNA complexes; the simulations also provide additional insights regarding why AlkB and ABH2 prefer single-strand and double-strand DNA, respectively, as substrate.

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Disruption and Formation of Surface Salt Bridges Are Coupled to DNA Binding by the Integration Host Factor: A Computational Analysis

Cited by 12 publications

References 47 publications

Phylogenetic and structural analyses reveal the determinants of DNA binding specificities of nucleoid-associated proteins HU and IHF

Phylogenetic and structural analyses reveal the determinants of DNA binding specificities of nucleoid-associated proteins HU and IHF

Salt bridge exchange binding mechanism between streptavidin and its DNA aptamer – thermodynamics and spectroscopic evidences

A simple but effective modeling strategy for structural properties of non‐heme Fe(II) sites in proteins: Test of force field models and application to proteins in the AlkB family

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