Anesthetic Interaction with Ketosteroid Isomerase: Insights from Molecular Dynamics Simulations

¹ University of Pittsburgh

^* To whom correspondence should be addressed. E-mail: tangp{at}anes.upmc.edu.

Submitted on March 23, 2005
Revised on May 24, 2005
Accepted on 14 July 2005

	Abstract

The nature and the sites of interactions between anesthetic halothane and homodimeric Delta(5)-3-Ketosteroid Isomerase (KSI) are characterized by flexible ligand docking and confirmed by 1H-15N NMR. The dynamics consequence of halothane interaction and the implication of the dynamic changes to KSI function are studied by multiple 5-ns molecular dynamics (MD) simulations in the presence and absence of halothane. Both docking and MD simulations show that halothane prefer the amphiphilic dimeric interface to the hydrophobic active site of KSI. Halothane occupancy at the dimer interface disrupted the inter-subunit hydrogen bonding formed either directly through side chains of polar residues or indirectly through the mediation of the interfacial water molecules. Moreover, in the presence of halothane, the exchange rate of the bound waters with bulk water was increased. Halothane perturbation to the dimer interface affected the overall flexibility of the active site. This action is likely to contribute to the halothane-induced reduction of the KSI activity. The allosteric halothane modulation of the dynamics-function relationship of KSI without direct competition at the enzymatic active sites may be generalized to offer a unifying explanation of anesthetic action on a diverse range of multi-domain neuronal proteins that are potentially relevant to clinical general anesthesia.

Key Words: Halothane, KSI, Molecular mechanisms of general anesthesia, drug protein interactions, ligand docking, molecular dynamics simulations

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