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001-es BibID:	BIBFORM055472
Első szerző:	Owen, Michael C.
Cím:	The Effect of Newly Developed OPLS-AA Alanyl Radical Parameters on Peptide Secondary Structure / Michael C. Owen, László Tóth, Balázs Jojárt, István Komáromi, Imre G. Csizmadia, Bela Viskolcz
Dátum:	2012
ISSN:	1549-9618
Megjegyzések:	Recent studies using ab initio calculations have-shown that C-alpha-centered radical formation by H-abstraction from the backbone of peptide residues has dramatic effects on peptide structure and have suggested that this reaction may contribute to the protein misfolding observed in Alzheimer's and Parkinson's diseases. To enable the effects of C-alpha-centered radicals to be studied in longer peptides and proteins over longer time intervals, force-field parameters for the C-alpha-centered Ala radical were developed for use with the OPLS force field by minimizing the sum of squares deviation between the quantum chemical and OPLS-AA energy hypersurfaces. These parameters were used to determine the effect of the C-alpha-centered Ala radical on the structure of a hepta-alanyl peptide in molecular dynamics (MD) simulations. A negligible sum-of-squares energy deviation was observed in the stretching parameters, and the newly developed OPLS-AA torsional parameters showed a good agreement with the LMP2/cc-pVTZ(-f) hypersurface. The parametrization also demonstrated that derived force-field bond length and bond angle parameters can deviate from the quantum chemical equilibrium values, and that the improper torsional parameters should be developed explicitly with respect to the coupled torsional parameters. The MD simulations showed planar conformations of the C-alpha-containing residue (Alr) are preferred and these conformations increase the formation of gamma-, alpha-, and pi-turn structures depending on the position in the turn occupied by the Alr residue. Higher-ordered structures are destabilized by Alr except when this residue occupies position "i + 1" of the 3(10)-helix. These results offer new insight into the protein-misfolding mechanisms initiated by H-abstraction from the C-alpha of peptide and protein residues.
Tárgyszavak:	Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Journal of Chemical Theory and Computation. - 8 : 8 (2012), p. 2569-2580. -
További szerzők:	Tóth László (1983-) (vegyész) Jójárt Balázs Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus) Csizmadia, Imre G. Viskolcz Béla
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001-es BibID:	BIBFORM056930
Első szerző:	Tóth László (vegyész)
Cím:	Dynamic properties of the native free antithrombin from molecular dynamics simulations : computational evidence for solvent- exposed Arg393 side chain / László Tóth, Attila Fekete, Gábor Balogh, Zsuzsanna Bereczky, István Komáromi
Dátum:	2015
ISSN:	0739-1102
Megjegyzések:	While antithrombin (AT) has small basal inhibitory activity, it reaches its full inhibitory potential against activated blood coagulation factors, FXa, FIXa, and FIIa (thrombin), via an allosteric and/or template (bridging) mechanism by the action of heparin, heparan sulfate, or heparin-mimetic pentasaccharides (PS). From the numerous X-ray structures available for different conformational states of AT, only indirect and incomplete conclusions can be drawn on the inherently dynamic properties of AT. As a typical example, the basal inhibitory activity of AT cannot be interpreted on the basis of "non-activated" free antithrombin X-ray structures since the Arg393 side chain, playing crucial role in antithrombin-proteinase interaction, is not exposed. In order to reveal the intrinsic dynamic properties and the reason of basal inhibitory activity of antithrombin, 2 ?s molecular dynamics simulations were carried out on its native free-forms. It was shown from the simulation trajectories that the reactive center loop which is functioning as "bait" for proteases, even without any biasing potential can populate conformational state in which the Arg393 side chain is solvent exposed. It is revealed from the trajectory analysis that the peptide sequences correspond to the helix D extension, and new helix P formation can be featured with especially large root-mean-square fluctuations. Mutual information analyses of the trajectory showed remarkable (generalized) correlation between those regions of antithrombin which changed their conformations as the consequence of AT-PS complex formation. This suggests that allosteric information propagation pathways are present even in the non-activated native form of AT.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban allostery antithrombin fluctuation generalized correlation molecular dynamics simulation principal component analysis reactive center loop serpin structure
Megjelenés:	Journal of Biomolecular Structure & Dynamics. - 33 : 9 (2015), p. 2023-2036. -
További szerzők:	Fekete Attila (1983-) (vegyész) Balogh Gábor (1991-) (gyógyszerész) Bereczky Zsuzsanna (1974-) (orvosi laboratóriumi diagnosztika szakorvos) Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus)
Pályázati támogatás:	K-106294 OTKA K-105459 OTKA PD-101120 OTKA TÁMOP-4.2.2.A-11/1/KONV-2012-0045 TÁMOP Trombózis Kutató Központ Kutatócsoport TÁMOP 4.2.4.A/2- 11-1-2012-0001 TÁMOP TAMOP-4.2.2.C-11/1/KONV-2012- 0010.1. TÁMOP NIIF-1057 Egyéb
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001-es BibID:	BIBFORM043596
Első szerző:	Tóth László (vegyész)
Cím:	Mechanism of the irreversible inhibition of human cyclooxygenase-1 by aspirin as predicted by QM/MM calculations / Tóth, L., Muszbek, L., Komáromi, I.
Dátum:	2013
ISSN:	1093-3263
Megjegyzések:	Acetylsalicylic acid (aspirin) suppresses the generation of prostaglandin H2, which is the precursor of thromboxane A2. Aspirin acts as an acetylating agent in which its acetyl group is covalently attached to a serine residue (S530) in the active site of the cyclooxygenase-1 enzyme. The exact reaction mechanism has not been revealed by experimental methods. In this study the putative structure of human cyclooxygenase-1 was constructed from ovine cyclooxygenase-1 by homology modeling, and the acetylsalicylic acid was docked into the arachidonic acid binding cavity of the enzyme. To characterize the shape of the potential energy surface of the acetylating reaction and to determine the relative energies of the stationary points on the surface, a series of ONIOM-type quantum mechanical/molecular mechanical (QM/MM) calculations were carried out at different QM levels of theories applying electronic embedding approximations. The acetylsalicylic acid and the surrounding amino acids were included in these calculations. Frequency analyses were performed to prove the existence of first order saddle points (representing transition states) and local minima on the potential energy surface. It was found that all levels of theories predicted similar transition state geometries. The activation energy values, however, demonstrated significant dependence on the methods that were applied. All the applied "dependable" ab initio and DFT methods predicted that the breakage of the S530 Ogamma--Hgamma and formation of the Ogamma--C(acetylsalicylic acid carbonyl) bonds occur in a single elementary step.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Doktori iskola
Megjelenés:	Journal Of Molecular Graphics & Modelling. - 40 (2013), p. 99-109. -
További szerzők:	Muszbek László (1942-) (haematológus, kutató orvos) Komáromi István (1957-) (vegyész, molekuláris biológus, biokémikus)
Pályázati támogatás:	NKFP-07-A1-2008-0127 Egyéb TÁMOP-4.2.2/B-10/1-2010-0024 TÁMOP Laki Kálmán Doktori Iskola MTA-DE MTA
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