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J. Biol. Chem., Vol. 281, Issue 14, 9432-9438, April 7, 2006

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Consequences of N-Acylation on Structure and Membrane Binding Properties of Dermaseptin Derivative K₄-S4-(1-13)^*

Deborah E. Shalev, Shahar Rotem, Alexander Fish, and Amram Mor¹

From the Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, Safra Campus, Givat Ram, 91904 Jerusalem, Israel and the Laboratory of Antimicrobial Peptides Investigation, Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, 32000 Haifa, Israel

Acyl conjugation to antimicrobial peptides is known to enhance antimicrobial properties. Here, we investigated the consequences of aminolauryl (NC₁₂) conjugation to the dermaseptin derivative K₄-S4-(1-13) (P) on binding properties to bilayer models mimicking bacterial plasma membrane, which is often cited as the ultimate site of action. Isothermal titration calorimetry revealed that acylation was responsible for enhancing the binding affinity of NC₁₂-P compared with P (K = 13 x 10⁵ and 1.5 x 10⁵ M^-1, respectively). Surface plasmon resonance measurements confirmed the isothermal titration calorimetry results (K_app = 12.6 x 10⁵ and 1.53 x 10⁵ M^-1, respectively) and further indicated that enhanced adhesion affinity (K_adhesion = 3 x 10⁵ and 1 x 10⁵ M^-1, respectively) was coupled to enhanced tendency to insert within the bilayer (K_insertion = 4.5 and 1.5, respectively). To gain insight into the molecular basis for these observations, we investigated the three-dimensional structures in the presence of dodecylphosphocholine using NMR. The ensemble of NMR-calculated structures (backbone root mean square deviation <0.6 Å) showed that the acyl moiety was responsible for a significant molecular reorganization, possibly affecting the electrostatic potential distribution in NC₁₂-P relative to that of P. The combined data present compelling evidence in support of the hypothesis that N-acylation affects antimicrobial properties by modifying the secondary structure of the peptide in a manner that facilitates contact with the membrane and consequently increases its disruption.

Received for publication, December 7, 2005 , and in revised form, December 30, 2005.

The atomic coordinates and structure factors (codes 2DD6 and 2DCX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This research was supported by Israel Science Foundation Grant 387/03. The Computer Graphics Laboratory (University of California, San Francisco) is supported by National Institutes of Health Grant P41 RR-01081. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains data on NOE interactions for P and NC₁₂-P in DPC in XPLOR format.

¹ To whom correspondence should be addressed. Tel.: 972-4-829-3340; Fax: 972-4-829-3399; E-mail: amor{at}tx.technion.ac.il.

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