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1.

001-es BibID:BIBFORM054068
Első szerző:Fuxreiter Mónika (kutató vegyész)
Cím:The role of reorganization energy in rational enzyme design / Monika Fuxreiter, Letif Mones
Dátum:2014
ISSN:1367-5931
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Current Opinion in Chemical Biology. - 21C (2014), p. 34-41. -
További szerzők:Mones, Letif
Pályázati támogatás:TÁMOP-4.2.2.C-11/1/KONV-2012-0010
TÁMOP
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2.

001-es BibID:BIBFORM049596
Első szerző:Lábas Anikó
Cím:Optimization of reorganization energy drives evolution of the designed Kemp eliminase KE07 / A. Labas, E. Szabo, L. Mones, M. Fuxreiter
Dátum:2013
ISSN:1570-9639
Megjegyzések:Understanding enzymatic evolution is essential to engineer enzymes with improved activities or to generate enzymes with tailor-made activities. The computationally designed Kemp eliminase KE07 carries out an unnatural reaction by converting of 5-nitrobenzisoxazole to cyanophenol, but its catalytic efficiency is significantly lower than those of natural enzymes. Three series of designed Kemp eliminases (KE07, KE70, KE59) were shown to be evolvable with considerable improvement in catalytic efficiency. Here we use the KE07 enzyme as a model system to reveal those forces, which govern enzymatic evolution and elucidate the key factors for improving activity. We applied the Empirical Valence Bond (EVB) method to construct the free energy pathway of the reaction in the original KE07 design and the evolved R7 1/3H variant. We analyzed catalytic effect of residues and demonstrated that not all mutations in evolution are favorable for activity. In contrast to the small decrease in the activation barrier, in vitro evolution significantly reduced the reorganization energy. We developed an algorithm to evaluate group contributions to the reorganization energy and used this approach to screen for KE07 variants with potential for improvement. We aimed to identify those mutations that facilitate enzymatic evolution, but might not directly increase catalytic efficiency. Computational results in accord with experimental data show that all mutations, which appear during in vitro evolution were either neutral or favorable for the reorganization energy. These results underscore that distant mutations can also play role in optimizing efficiency via their contribution to the reorganization energy. Exploiting this principle could be a promising strategy for computer-aided enzyme design. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1834 : 5 (2013), p. 908-917. -
További szerzők:Szabó E. Mones, Letif Fuxreiter Mónika (1969-) (kutató vegyész)
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3.

001-es BibID:BIBFORM031423
Első szerző:Mones, Letif
Cím:The energy gap as a universal reaction coordinate for the simulation of chemical reactions / Letif Mones, Petr Kulhánek, István Simon, Alessandro Laio, Monika Fuxreiter
Dátum:2009
ISSN:1520-6106
Megjegyzések:The selection of a proper reaction coordinate is a major bottleneck in simulations of chemical reactions in complex systems. Increasing the number of variables that are used to bias the reaction largely affects the convergence and leads to an unbearable increase in computational price. This problem can be overcome by employing a complex reaction coordinate that depends on many geometrical variables of the system, such as the energy gap (EGAP) in the empirical valence bond (EVB) method. EGAP depends on all of the coordinates of the system, and its robustness has been demonstrated for a variety of enzymatic reactions. In this work, we demonstrate that EGAP, derived from a classical representation, can be used as a reaction coordinate in systems described with any quantum chemistry Hamiltonian. Benefits of using EGAP as a reaction coordinate as compared to a traditional geometrical variable are illustrated in the case of a symmetric nucleophilic substitution reaction in water solution. EGAP is shown to provide a significantly more efficient sampling and allows a better localization of the transition state as compared to a geometrical reaction coordinate.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:The Journal of Physical Chemistry. B. - 113 : 22 (2009), p. 7867-7873. -
További szerzők:Kulhánek, Petr Simon István Laio, Alessandro Fuxreiter Mónika (1969-) (kutató vegyész)
Pályázati támogatás:K72569
OTKA
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4.

001-es BibID:BIBFORM031412
035-os BibID:PMID:18020376 WOS:000251547700018
Első szerző:Mones, Letif
Cím:Probing the two-metal ion mechanism in the restriction endonuclease BamHI / Letif Mones, Petr Kulhánek, Jan Florián, István Simon, Monika Fuxreiter
Dátum:2007
ISSN:0006-2960
Megjegyzések:The choreography of restriction endonuclease catalysis is a long-standing paradigm in molecular biology. Bivalent metal ions are required almost for all PD..D/ExK type enzymes, but the number of cofactors essential for the DNA backbone scission remained ambiguous. On the basis of crystal structures and biochemical data for various restriction enzymes, three models have been developed that assign critical roles for one, two, or three metal ions during the phosphodiester hydrolysis. To resolve this apparent controversy, we investigated the mechanism of BamHI catalysis using quantum mechanical/molecular mechanical simulation techniques and determined the activation barriers of three possible pathways that involve a Glu-113 or a neighboring water molecule as a general base or an external nucleophile that penetrated from bulk solution. The extrinsic mechanism was found to be the most favorable with an activation free energy of 23.4 kcal/mol, in reasonable agreement with the experimental data. On the basis of the effect of the individual metal ions on the activation barrier, metal ion A was concluded to be pivotal for the reaction, while the enzyme lacking metal ion B still has moderate efficiency. Thus, we propose that the catalytic scheme of BamHI does not involve a general base for nucleophile generation and requires one obligatory metal ion for catalysis that stabilizes the attacking nucleophile and coordinates it throughout the nucleophilic attack. Such a model may also explain the variation in the number of metal ions in the crystal structures and thus could serve as a framework for a unified catalytic scheme of type II restriction endonucleases.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Biochemistry. - 46 : 50 (2007), p. 14514-14523. -
További szerzők:Kulhánek, Petr Florián, Jan Simon István Fuxreiter Mónika (1969-) (kutató vegyész)
Pályázati támogatás:T049073
OTKA
F046164
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5.

001-es BibID:BIBFORM031407
035-os BibID:WOS:000243366400009 PMID:17214552
Első szerző:Mones, Letif
Cím:Metal-binding sites at the active site of restriction endonuclease BamHI can conform to a one-ion mechanism / Letif Mones, István Simon, Monika Fuxreiter
Dátum:2007
ISSN:1431-6730
Megjegyzések:The number of metal ions required for phosphoryl transfer in restriction endonucleases is still an unresolved question in molecular biology. The two Ca2+ and Mn2+ ions observed in the pre- and post-reactive complexes of BamHI conform to the classical two-metal ion choreography. We probed the Mg2+ cofactor positions at the active site of BamHI by molecular dynamics simulations with one and two metal ions present and identified several catalytically relevant sites. These can mark the pathway of a single ion during catalysis, suggesting its critical role, while a regulatory function is proposed for a possible second ion.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
egyetemen (Magyarországon) készült közlemény
Megjelenés:Biological chemistry. - 388 : 1 (2007), p. 73-78. -
További szerzők:Simon István Fuxreiter Mónika (1969-) (kutató vegyész)
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6.

001-es BibID:BIBFORM031395
035-os BibID:PMID:19682999 WOS:000271341400011
Első szerző:Pingoud, Vera
Cím:On the divalent metal ion dependence of DNA cleavage by restriction endonucleases of the EcoRI family / Vera Pingoud, Wolfgang Wende, Peter Friedhoff, Monika Reuter, Jürgen Alves, Albert Jeltsch, Letif Mones, Monika Fuxreiter, Alfred Pingoud
Dátum:2009
Megjegyzések:Restriction endonucleases of the PD...D/EXK family need Mg(2+) for DNA cleavage. Whereas Mg(2+) (or Mn(2+)) promotes catalysis, Ca(2+) (without Mg(2+)) only supports DNA binding. The role of Mg(2+) in DNA cleavage by restriction endonucleases has elicited many hypotheses, differing mainly in the number of Mg(2+) involved in catalysis. To address this problem, we measured the Mg(2+) and Mn(2+) concentration dependence of DNA cleavage by BamHI, BglII, Cfr10I, EcoRI, EcoRII (catalytic domain), MboI, NgoMIV, PspGI, and SsoII, which were reported in co-crystal structure analyses to bind one (BglII and EcoRI) or two (BamHI and NgoMIV) Me(2+) per active site. DNA cleavage experiments were carried out at various Mg(2+) and Mn(2+) concentrations at constant ionic strength. All enzymes show a qualitatively similar Mg(2+) and Mn(2+) concentration dependence. In general, the Mg(2+) concentration optimum (between approximately 1 and 10 mM) is higher than the Mn(2+) concentration optimum (between approximately 0.1 and 1 mM). At still higher Mg(2+) or Mn(2+) concentrations, the activities of all enzymes tested are reduced but can be reactivated by Ca(2+). Based on these results, we propose that one Mg(2+) or Mn(2+) is critical for restriction enzyme activation, and binding of a second Me(2+) plays a role in modulating the activity. Steady-state kinetics carried out with EcoRI and BamHI suggest that binding of a second Mg(2+) or Mn(2+) mainly leads to an increase in K(m), such that the inhibitory effect of excess Mg(2+) or Mn(2+) can be overcome by increasing the substrate concentration. Our conclusions are supported by molecular dynamics simulations and are consistent with the structural observations of both one and two Me(2+) binding to these enzymes.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Journal of molecular biology. - 393 : 1 (2009), p. 140-160. -
További szerzők:Wende, Wolfgang Friedhoff, Peter Reuter Mónika Alves, Jürgen Jeltsch, Albert Mones, Letif Fuxreiter Mónika (1969-) (kutató vegyész) Pingoud, Alfred
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