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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:	BIBFORM031427
035-os BibID:	PMID:19919153 WOS:000271272000005
Első szerző:	Tóth-Petróczy Ágnes
Cím:	Disordered tails of homeodomains facilitate DNA recognition by providing a trade-off between folding and specific binding / Ágnes Tóth-Petróczy, Istvan Simon, Monika Fuxreiter, Yaakov Levy
Dátum:	2009
ISSN:	0002-7863
Megjegyzések:	DNA binding specificity of homeodomain transcription factors is critically affected by disordered N-terminal tails (N-tails) that undergo a disorder-to-order transition upon interacting with DNA. The mechanism of the binding process and the molecular basis of selectivity are largely unknown. The coupling between folding and DNA binding of Antp and NK-2 homeodomains was investigated by coarse-grained molecular dynamics simulations using the native protein-DNA complex. The disordered N-tails were found to decrease the stability of the free proteins by competing with the native intramolecular interactions and increasing the radius of gyration of the homeodomain cores. In the presence of DNA, however, the N-tails increase the stability of the homeodomains by reducing the coupling between folding and DNA binding. Detailed studies on Antp demonstrate that the N-tail anchors the homeodomain to DNA and accelerates formation of specific interactions all along the protein-DNA interface. The tidal electrostatic forces between the N-tail and DNA induce faster and tighter binding of the homeodomain core to the DNA; this mechanism conforms to a fly-casting mechanism. In agreement with experiments, the N-tail of Antp also improves the binding affinity for DNA, with a major contribution by the released waters. These results imply that varying the degree of folding upon binding and thereby modulating the size of the buried surface-disordered N-tails of homeodomains can fine-tune the binding strength for specific DNA sequences. Overall, both the kinetics and thermodynamics of specific DNA binding by homeodomains can be improved by N-tails using a mechanism that is inherent in their disordered state.
Tárgyszavak:	Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban külföldön készült közlemény
Megjelenés:	Journal of the American Chemical Society. - 131 : 42 (2009), p. 15084-15085. -
További szerzők:	Simon István Fuxreiter Mónika (1969-) (kutató vegyész) Levy, Yaakov
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat DOI
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