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001-es BibID:	BIBFORM122753
035-os BibID:	(WoS)85197183804 (Scopus)85197183804
Első szerző:	Balogh Gábor
Cím:	Molecular Mechanisms of the Impaired Heparin Pentasaccharide Interactions in 10 Antithrombin Heparin Binding Site Mutants Revealed by Enhanced Sampling Molecular Dynamics / Gábor Balogh, Zsuzsanna Bereczky
Dátum:	2024
ISSN:	2218-273X
Megjegyzések:	Antithrombin (AT) is a critical regulator of the coagulation cascade by inhibiting multiple coagulation factors including thrombin and FXa. Binding of heparinoids to this serpin enhances the inhibition considerably. Mutations located in the heparin binding site of AT result in thrombophilia in affected individuals. Our aim was to study 10 antithrombin mutations known to affect their heparin binding in a heparin pentasaccharide bound state using two molecular dynamics (MD) based methods providing enhanced sampling, GaMD and LiGaMD2. The latter provides an additional boost to the ligand and the most important binding site residues. From our GaMD simulations we were able to identify four variants (three affecting amino acid Arg47 and one affecting Lys114) that have a particularly large effect on binding. The additional acceleration provided by LiGaMD2 allowed us to study the consequences of several other mutants including those affecting Arg13 and Arg129. We were able to identify several conformational types by cluster analysis. Analysis of the simulation trajectories revealed the causes of the impaired pentasaccharide binding including pentasaccharide subunit conformational changes and altered allosteric pathways in the AT protein. Our results provide insights into the effects of AT mutations interfering with heparin binding at an atomic level and can facilitate the design or interpretation of in vitro experiments.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk antithrombin mutations molecular dynamics enhanced sampling simulation methods
Megjelenés:	Biomolecules. - 14 : 6 (2024), p. 1-22. -
További szerzők:	Bereczky Zsuzsanna (1974-) (orvosi laboratóriumi diagnosztika szakorvos)
Pályázati támogatás:	OTKA K-139293 OTKA OTKA-106294 OTKA OTKA-116228 OTKA
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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