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001-es BibID:	BIBFORM031437
035-os BibID:	(WoS)000071510300025 (Scopus)84962422582
Első szerző:	Fuxreiter Mónika (kutató vegyész)
Cím:	Origin of the catalytic power of acetylcholinesterase : computer simulation studies / Monika Fuxreiter, Arieh Warshel
Dátum:	1998
ISSN:	0002-7863
Megjegyzések:	The energetics of the acylation step of AChE (acetylcholinesterase) is explored by using molecular simulation approaches. These include the evaluation of activation free energies by using the empirical valence bond (EVE) potential surface and an all-atom free energy perturbation (FEP) approach, as well as estimates of the catalytic effect of the enzyme by using the semimicroscopic version of the Protein Dipoles Langevin Dipoles (PDLD/S) method. The determination of the effect of the enzyme is based on the use of reliable experimental information in evaluating the energetics of the reference reaction in water and then on using robust simulations for the evaluation of the effect of moving the reacting system from a solvent cage to the protein active site. This procedure reduces the error range of the overall analysis since the energetics in water is not evaluated by a first principle approach. The use of two simulation methods and different initial conditions provide a way for assessing the error range of the calculations and the validity of the corresponding conclusions. Both the EVE and PDLD/S approaches show that the enzyme reduces the activation barrier of the acylation step by 10-15 kcal/mol relative to the corresponding reference reaction in water. This corresponds to a (10(7)-10(11))-fold rate acceleration, which is in good agreement with the corresponding experimental estimate. The origin of the catalytic power of the enzyme appears to be associated with electrostatic stabilization of the transition state. This electrostatic effect can be classified as a combination of reduction of the energy of the charged intermediate and reduction in the reorganization energy. The contributions of different protein residues to the stabilization of the transition state are estimated. It is demonstrated that, in contrast to some proposals, AChE and other enzymes do not work by providing a hydrophobic environment but rather a polar environment. This work concludes that the most important catalytic effects are associated with nearby residues rather than distant ionized residues. It is also concluded that the enzyme has evolved first to optimize the speed of the actual bond breaking/bond making chemical processes and only then to fine-tune the rate by optimizing the barrier for the diffusion step. Since the optimization of the chemical step involves more than 10 kcal/mol and the optimization of the diffusion step involves at most 1 or 2 kcal/mol, it appears that the possible acceleration of the diffusion step is a second-order effect. These conclusions are consistent with the available experimental studies.
Tárgyszavak:	Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Journal of the American Chemical Society. - 120 : 1 (1998), p. 183-194. -
További szerzők:	Warshel, Arieh
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat DOI
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001-es BibID:	BIBFORM031390
035-os BibID:	(Scopus)0033609515 (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 Szerző által megadott URL DOI
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001-es BibID:	BIBFORM054887
Első szerző:	Náray-Szabó Gábor
Cím:	Electrostatic basis of enzyme catalysis / G. Náray-Szabó, M. Fuxreiter, A. Warshel
Dátum:	1997
ISBN:	0-7923-4512-6
Tárgyszavak:	Orvostudományok Elméleti orvostudományok könyvfejezet
Megjelenés:	Computational approaches to biochemical reactivity / ed. by Gábor Náray-Szabó, Arieh Warshel. - p. 237-293. -
További szerzők:	Fuxreiter Mónika (1969-) (kutató vegyész) Warshel, Arieh
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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