Docking, molecular dynamics and QM/MM studies to delineate the mode of binding of CucurbitacinE to F-actin

Kumar, Pravin R and Roopa, L and Nongthomba, Upendra and Mohammed, Sudheer MM and Kulkarni, Naveen (2016) Docking, molecular dynamics and QM/MM studies to delineate the mode of binding of CucurbitacinE to F-actin. In: JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 63 . pp. 29-37.

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Abstract

CucurbitacinE (CurE) has been known to bind covalently to F-actin and inhibit depolymerization. However, the mode of binding of CurE to F-actin and the consequent changes in the F-actin dynamics have not been studied. Through quantum mechanical/molecular mechanical (QM/MM) and density function theory (DFT) simulations after the molecular dynamics (MD) simulations of the docked complex of F-actin and CurE, a detailed transition state (TS) model for the Michael reaction is proposed. The TS model shows nucleophilic attack of the sulphur of Cys257 at the beta-carbon of Michael Acceptor of CurE producing an enol intermediate that forms a covalent bond with CurE. The MD results show a clear difference between the structure of the F-actin in free form and F-actin complexed with CurE. CurE affects the conformation of the nucleotide binding pocket increasing the binding affinity between F-actin and ADP, which in turn could affect the nucleotide exchange. CurE binding also limits the correlated displacement of the relatively flexible domain 1 of F-actin causing the protein to retain a flat structure and to transform into a stable ``tense'' state. This structural transition could inhibit depolymerization of F-actin. In conclusion, CurE allosterically modulates ADP and stabilizes F-actin structure, thereby affecting nucleotide exchange and depolymerization of F-actin. (C) 2015 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Publication:	JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Publisher:	ELSEVIER SCIENCE INC
Additional Information:	Copy right for this article belongs to the ELSEVIER SCIENCE INC, 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Keywords:	Actin depolymerization; Cucurbitacin; DFT simulation; Motional correlation; Quantum mechanics
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	03 Mar 2016 06:06
Last Modified:	03 Mar 2016 06:06
URI:	http://eprints.iisc.ac.in/id/eprint/53368

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