Molecular dynamics simulation of trp-repressor/operator complex: analysis of hydrogen bond patterns of protein–DNA interaction

Is it by design or by default that water molecules are observed at the interfaces of some protein-DNA complexes? Both experimental and theoretical studies on the thermodynamics of protein-DNA binding overwhelmingly support the extended hydrophobic view that water release from interfaces favors binding. Structural and energy analyses indicate that the waters that remain at the interfaces of protein-DNA complexes ensure liquid-state packing densities, screen the electrostatic repulsions between like charges (which seems to be by design), and in a few cases act as linkers between complementary charges on the biomolecules (which may well be by default). This review presents a survey of the current literature on water in protein-DNA complexes and a critique of various interpretations of the data in the context of the role of water in protein-DNA binding and principles of protein-DNA recognition in general.

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“…Simulation studies (34,38,80,120,128,132,146) in general have supported the crystallographic/NMR observations on water-mediated hydrogen bonds.…”

Section: Water In Protein-dna Bindingsupporting

confidence: 59%

The Role of Water in Protein-DNA Recognition

Jayaram

Jain

2004

Annu. Rev. Biophys. Biomol. Struct.

193

162

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“…9 On the other hand, it was observed, that the hydration of the uncomplexed trp operator does not seem to be preorganized or kinetically stabilized to match in the complex. 24 Two short molecular dynamics simulations 25,26 of the trp-repressor operator complex performed previously reproduced well the water-mediated contacts observed in crystal 5 structures of the trp-repressor operator complex. In their time scale of simulations, they could not present dynamic properties of the water-mediated contacts.…”

Section: Introductionsupporting

confidence: 57%

“…Two short MD simulations 25,26 have proven their ability to reproduce water-mediated contacts of trprepressor operator complex as seen in crystal 5 structure. Though, in these simulations all crystal water molecules were removed, the applied simulation protocols allowed the adjustment of these contacts.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular dynamics (MD) simulations of biologically interesting macromolecules such as DNA [27][28][29][30] and protein-DNA complexes 18,26,31 have proven to be a valuable tool for a deeper understanding of structural and dynamical properties. The inclusion of the long-range interactions via the Ewald summation in form of the so-called particle mesh Ewald method allows the calculation of stable B-form DNA trajectories [32][33][34] in the nanosecond time range.…”

Section: Methodsmentioning

confidence: 99%

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Water‐mediated contacts in thetrp‐repressor operator complex recognition process

et al. 2004

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Water-mediated contacts are known as an important recognition tool in trp-repressor operator systems. One of these contacts involves two conserved base pairs (G(6).C(-6) and A(5). T(-5)) and three amino acids (Lys 72, Ile 79, and Ala 80). To investigate the nature of these contacts, we analyzed the X-ray structure (PDB code: 1TRO) of the trp-repressor operator complex by means of molecular dynamics simulations. This X-ray structure contains two dimers that exhibit structural differences. From these two different starting structures, two 10 ns molecular dynamics simulations have been performed. Both of our simulations show an increase of water molecules in the major groove at one side of the dimer, while the other side remains unchanged compared to the X-ray structure. Though the maximum residence time of the concerned water molecules decreases with an increase of solvent at the interface, these water molecules continue to play an important role in mediating DNA-protein contacts. This is shown by new stable amino acids-DNA distances and a long water residence time compared to free DNA simulation. To maintain stability of the new contacts, the preferential water binding site on O6(G6) is extended. This extension agrees with mutation experiment data on A5 and G6, which shows different relative affinity due to mutation on these bases [A. Joachimiak, T. E. Haran, P. B. Sigler, EMBO Journal 1994, Vol. 13, No. (2) pp. 367-372]. Due to the rearrangements in the system, the phosphate of the base G6 is able to interconvert to the B(II) substate, which is not observed on the other half side of the complex. The decrease of the number of hydrogen bonds between protein and DNA backbone could be the initial step of the dissociation process of the complex, or in other words an intermediate complex conformation of the association process. Thus, we surmise that these features show the importance of water-mediated contacts in the trp-repressor operator recognition process.

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“…The first studies utilizing this technique involved analysis of correlated motions in cytochrome c (McCammon, 1984), ribonuclease A with two different substrates (Brünger et al, 1985), HIV-1 protease (Harte et al, 1990;Harte et al, 1992;Swaminathan et al, 1991), and BPTI (Ichiye and Karplus, 1991). Since these pioneering studies, cross-correlations and DCCMs have been used to analyze the fluctuations of many diverse systems, including proteins (Arcangeli et al, 1999;Parchment and Essex, 2000;Arcangeli et al, 2001;Rizzuti et al, 2001;Young et al, 2001;Luo and Bruice, 2002;Zoete et al, 2002), protein-nucleic acid complexes (Suenaga et al, 2000;Trylska et al, 2005), and enzymes (Bahar et al, 1997;Radkiewicz and Brooks III, 2000;Rod et al, 2003;Sulpizi et al, 2003;Agarwal, 2004;Gunasekaran and Nussinov, 2004;Schiøtt, 2004;Wong et al, 2004;Fuxreiter et al, 2005;Gorfe and Caflisch, 2005;Ma et al, 2005). A recent study analyzing both the B1 domain of protein G and ubiquitin suggests the correlated motions obtained from MD simulations agree well with measured NMR data (Lange et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

Kormos

Baranger

Beveridge

2007

Journal of Structural Biology

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Cooperative interactions play an important role in recognition and binding in macromolecular systems. In this study, we find that cross-correlated fluctuations can be used to identify cooperative networks in a protein-RNA system. The dynamics of the RRM-containing protein U1A-stem loop 2 RNA complex have been calculated theoretically from a 10 ns molecular dynamics (MD) simulation. The simulation was analyzed by calculating the covariance matrix of all atomic fluctuations. These matrix elements are then presented in the form of a two-dimensional grid, which displays fluctuations on a per-residue basis. The results indicate the presence of strong, selective cross-correlated fluctuations throughout the RRM in U1A-RNA, which correspond well with the results from a statistical covariance analysis of 330 aligned RRM sequences and previous biophysical studies in which a multiplicity of cooperative networks have been reported. Moreover, the MD results indicate that the various networks identified in separate individual experiments are fluctuationally correlated into a hyper-network encompassing most of the RRM. This method has significant implications as a predictive tool regarding cooperativity in the protein-nucleic acid recognition process.

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Molecular dynamics simulation of trp-repressor/operator complex: analysis of hydrogen bond patterns of protein–DNA interaction

Cited by 16 publications

References 45 publications

The Role of Water in Protein-DNA Recognition

The Role of Water in Protein-DNA Recognition

Water‐mediated contacts in thetrp‐repressor operator complex recognition process

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

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