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1.

001-es BibID:BIBFORM031428
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Computational approaches to restriction endonucleases / M. Fuxreiter, R. Osman, I. Simon
Dátum:2004
Tárgyszavak:Természettudományok Biológiai tudományok előadáskivonat
Megjelenés:The Role of Chemistry in the Evolution of Molecular Medicine : Proceedings of the symposium held at the University of Szeged to celebrate the 110th birthday of Professor Albert Szent-Györgyi 2003.06.27-2003.06.29 Magyarország, Szeged / eds. Imre Csizmadia, Botond Penke, Gábor Toth. - p. 469-480. -
További szerzők:Osman, Roman Simon István
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2.

001-es BibID:BIBFORM031404
035-os BibID:WOS:000230822200016
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Interfacial Water as a "Hydration Fingerprint" in the Noncognate Complex of BamHI / Monika Fuxreiter, Mihaly Mezei, István Simon, Roman Osman
Dátum:2005
ISSN:0006-3495
Megjegyzések:The molecular code of specific DNA recognition by proteins as a paradigm in molecular biology remains an unsolved puzzle primarily because of the subtle interplay between direct protein-DNA interaction and the indirect contribution from water and ions. Transformation of the nonspecific, low affinity complex to a specific, high affinity complex is accompanied by the release of interfacial water molecules. To provide insight into the conversion from the loose to the tight form, we characterized the structure and energetics of water at the protein-DNA interface of the BamHI complex with a noncognate sequence and in the specific complex. The fully hydrated models were produced with Grand Canonical Monte Carlo simulations. Proximity analysis shows that water distributions exhibit sequence dependent variations in both complexes and, in particular, in the noncognate complex they discriminate between the correct and the star site. Variations in water distributions control the number of water molecules released from a given sequence upon transformation from the loose to the tight complex as well as the local entropy contribution to the binding free energy. We propose that interfacial waters can serve as a "hydration fingerprint'' of a given DNA sequence.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Biophysical Journal. - 89 : 2 (2005), p. 903-911. -
További szerzők:Mezei Mihály Simon István Osman, Roman
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM031402
035-os BibID:WOS:000188928800053
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Computational approaches to restriction endonucleases / M. Fuxreiter, R. Osman, I. Simon
Dátum:2003
ISSN:0166-1280
Megjegyzések:Type II restriction endonucleases catalyze phosphodiester bond hydrolysis in bacteria to protect the host cell from invading phage DNA. Due to their exquisite sequence selectivity type II restriction endonucleases serve as excellent model systems for studying protein-nucleic acid interactions. Crystal structures of the PD-(D/E)XK superfamily revealed a common alpha/beta core motif and similar active site. In contrast, these enzymes show little sequence similarity and use different strategies to interact with their substrate DNA. Computational approaches have been applied to unify the mechanism of restriction endonucleases and rationalize their diversity. The first step of type II restriction endonuclease catalysis has been studied on Bam HI by semi-microscopic version of the Protein Dipoles Langevin Dipoles method. The substrate-assisted catalysis and the general base mechanism have been concluded as less likely than the metal-catalyzed reaction. A general model for catalysis has been proposed based on the group contributions to the reduction of the activation free energy. Factors contributing to structural stability of PD-(D/E)XK type II restriction endonucleases have been analyzed to elucidate evolutionary relationship between these enzymes. Residues playing role in catalysis and recognition were highly correlated with those participating in stabilization centers. Thus the main functional motifs were concluded to be evolutionary more conserved than other parts of the structure. This observation is consistent with the proposal that these enzymes have developed from a common ancestor with divergent evolution.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Journal of molecular structure. - 666-667 (2003), p. 469-479. -
További szerzők:Osman, Roman Simon István
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
DOI
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4.

001-es BibID:BIBFORM031398
035-os BibID:PMID:12417196 WOS:000179308500004
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Role of base flipping in specific recognition of damaged DNA by repair enzymes / Monika Fuxreiter, Ning Luo, Pál Jedlovszky, István Simon, Roman Osman
Dátum:2002
Megjegyzések:DNA repair enzymes induce base flipping in the process of damage recognition. Endonuclease V initiates the repair of cis, syn thymine dimers (TD) produced in DNA by UV radiation. The enzyme is known to flip the base opposite the damage into a non-specific binding pocket inside the protein. Uracil DNA glycosylase removes a uracil base from G.U mismatches in DNA by initially flipping it into a highly specific pocket in the enzyme. The contribution of base flipping to specific recognition has been studied by molecular dynamics simulations on the closed and open states of undamaged and damaged models of DNA. Analysis of the distributions of bending and opening angles indicates that enhanced base flipping originates in increased flexibility of the damaged DNA and the lowering of the energy difference between the closed and open states. The increased flexibility of the damaged DNA gives rise to a DNA more susceptible to distortions induced by the enzyme, which lowers the barrier for base flipping. The free energy profile of the base-flipping process was constructed using a potential of mean force representation. The barrier for TD-containing DNA is 2.5 kcal mol(-1) lower than that in the undamaged DNA, while the barrier for uracil flipping is 11.6 kcal mol(-1) lower than the barrier for flipping a cytosine base in the undamaged DNA. The final barriers for base flipping are approximately 10 kcal mol(-1), making the rate of base flipping similar to the rate of linear scanning of proteins on DNA. These results suggest that damage recognition based on lowering the barrier for base flipping can provide a general mechanism for other DNA-repair enzymes.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Journal of molecular biology. - 323 : 5 (2002), p. 823-834. -
További szerzők:Luo, Ning Jedlovszky Pál Simon István Osman, Roman
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM031392
035-os BibID:PMID:11732923 WOS:000172608100033
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Probing the general base catalysis in the first step of BamHI action by computer simulations / Monika Fuxreiter, Roman Osman
Dátum:2001
ISSN:0006-2960
Megjegyzések:BamHI is a type II restriction endonuclease that catalyzes the scission of the phoshodiester bond in the GAGTCC cognate sequence in the presence of two divalent metal ions. The first step of the reaction is the preparation of water for nucleophilic attack by Glu-113, which has been proposed to abstract the proton from the attacking water molecule. Alternatively, the 3'-phosphate group to the susceptible phosphodiester bond has been suggested to play a role as the general base. The two hypotheses have been tested by computer simulations using the semiempirical protein dipoles Langevin dipoles (PDLD/S) method. Deprotonation of water by Glu-113 has been found to be less favorable by 5.7 kcal/mol than metal-catalyzed deprotonation with a concomitant proton transfer to bulk solvent. The preparation of the nucleophile by the 3'-phosphate group is less favorable by 12.3 kcal/mol. These results suggest that both the general base and the substrate-assisted mechanisms in the first step of BamHI action are less likely than the metal-catalyzed reaction. The metal ions in the active site of BamHI make the largest contributions to the reduction of the free energy of hydroxide ion formation. On the basis of these findings we propose that the first step of endonuclease catalysis does not require a general base; rather, the essential attacking nucleophile in BamHI catalytic action is stabilized by the metal ions.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Biochemistry. - 40 : 49 (2001), p. 15017-15023. -
További szerzők:Osman, Roman
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
DOI
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6.

001-es BibID:BIBFORM031390
035-os BibID:PMID:10423235 WOS:000081768900004
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:Role of active site residues in the glycosylase step of T4 endonuclease V. Computer simulation studies on ionization states / Monika Fuxreiter, Arieh Warshel, Roman Osman
Dátum:1999
ISSN:0006-2960
Megjegyzések:T4 Endonuclease V (EndoV) is a base excision repair enzyme that removes thymine dimers (TD) from damaged DNA. To elucidate the role of the active site residues in catalysis, their pK(a)'s were evaluated using the semimicroscopic version of the protein dipoles-Langevin dipoles method (PDLD/S). Contributions of different effects to the pK(a) such as charge-charge interactions, conformational rearrangement, protein relaxation, and DNA binding were analyzed in detail. Charging of the active site residues was found to be less favorable in the complex than in the free enzyme. The pK(a) of the N-terminus decreased from 8.01 in the free enzyme to 6.52 in the complex, while the pK(a) of Glu-23 increased from 1. 52 to 7.82, which indicates that the key residues are neutral in the reactant state of the glycosylase step. These pK(a)'s are in agreement with the optimal pH range of the reaction and support the N-terminus acting as a nucleophile. The Glu-23 in its protonated form is hydrogen bonded to O4' of the sugar of 5' TD and can play a role in increasing the positive charge of C1' and, hence, accelerating the nucleophilic substitution. Furthermore, the neutral Glu-23 is a likely candidate to protonate O4' to induce ring opening required to complete the glycosylase step of EndoV. The positively charged Arg-22 and Arg-26 provide an electrostatically favorable environment for the leaving base. To distinguish between S(N)1 and S(N)2 mechanisms of the glycosylase step the energetics of protonating O2 of 5' TD was calculated. The enzyme was found to stabilize the neutral thymine by approximately 3.6 kcal/mol, whereas it destabilizes the protonated thymine by approximately 6.6 kcal/mol with respect to an aqueous environment. Consequently, the formation of a protonated thymine intermediate is unlikely, indicating an S(N)2 reaction mechanism for the glycosylase step.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Biochemistry. - 38 : 30 (1999), p. 9577-9589. -
További szerzők:Warshel, Arieh Osman, Roman
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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7.

001-es BibID:BIBFORM031391
035-os BibID:PMID:10816003 WOS:000086871300011
Első szerző:Osman, Roman
Cím:Specificity of damage recognition and catalysis of DNA repair / R. Osman, M. Fuxreiter, N. Luo
Dátum:2000
ISSN:0097-8485
Megjegyzések:A common feature of DNA repair enzymes is their ability to recognize the damage independently of sequence in which they are found. The presence of a flipped out base inserted into the protein in several DNA-enzyme complexes suggests a contribution to enzyme specificity. Molecular simulations of damaged DNA indicate that the damage produces changes in DNA structure and changes the dynamics of DNA bending. The reduced bending force constant can be used by the enzyme to induce DNA bending and facilitate base flipping. We show that a thymine dimer (TD) containing DNA requires less energy to bend, lowering the barrier for base flipping. On the other hand, bending in DNA with U-G mismatch is affected only by a small amount and flipping is not enhanced significantly. T4 endonuclease V (endoV), which recognizes TD, utilizes the reduced barrier for flipping as a specific recognition element. In uracil DNA glycosylase (UDG), which recognizes U-G mismatches, base flipping is not enhanced and recognition is encoded in a highly specific binding pocket for the flipped base. Simulations of UDG and endoV in complex with damaged DNA provide insight into the essential elements of the catalytic mechanism. Calculations of pKas of active site residues in endoV and endoV-DNA complex show that the pKa, of the N-terminus is reduced from 8.01 to 6.52 while that of Glu-23 increases from 1.52 to 7.82. Thus, the key catalytic residues are in their neutral form. The simulations also show that Glu-23 is also H-bonded to O4' of the 5'-TD enhancing the nucleophilic attack on Cl and that Arg-26 enhances the hydrolysis by electrostatic stabilization but does not participate in proton transfer. In the enzyme-substrate complex of UDG, the role of electrostatic stabilization is played by His-268, whose pKa increases to 7.1 from 4.9 in the free enzyme. The pKa of Asp-145, the other important catalytic residue, remains around 4.2 in the free enzyme and in the complex. Thus, it can not act as a proton acceptor. In the complex the 3'-phosphate of uracil is stabilized next to Asp-145 by two bridging water molecules. Such a configuration activates one water molecule to act as a proton acceptor to produce a stabilizing hydronium ion and the other as a proton donor to produce the nucleophilic hydroxide. It appears that DNA glycosylases share commonalties in recognition of damage but differ in their catalytic mechanisms.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Computers & Chemistry. - 24 : 3-4 (2000), p. 331-339. -
További szerzők:Fuxreiter Mónika (1969-) (kutató vegyész) Luo, Ning
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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