Modelling study of dimerization in mammalian defensins

BackgroundDefensins are antimicrobial peptides of innate immunity functioning by non-specific binding to anionic phospholipids in bacterial membranes. Their cationicity, amphipathicity and ability to oligomerize are considered key factors for their action. Based on structural information on human β-defensin 2, we examine homologous defensins from various mammalian species for conserved functional physico-chemical characteristics.ResultsBased on homology greater than 40%, structural models of 8 homologs of HBD-2 were constructed. A conserved pattern of electrostatics and dynamics was observed across 6 of the examined defensins; models backed by energetics suggest that the defensins in these 6 organisms are characterized by dimerization-linked enhanced functional potentials. In contrast, dimerization is not energetically favoured in the sheep, goat and mouse defensins, suggesting that they function efficiently as monomers.Conclusionβ-defensin 2 from some mammals may work as monomers while those in others, including humans, work as oligomers. This could potentially be used to design human defensins that may be effective at lower concentrations and hence have therapeutic benefits.

[1]  K. Brogden.  Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? , 2005, Nature Reviews Microbiology.

[2]  Adrian A Canutescu,et al.  Access the most recent version at doi: 10.1110/ps.03154503 References , 2003 .

[3]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[4]  J. Lubkowski,et al.  Reconstruction of the Conserved β-Bulge in Mammalian Defensins Using d-Amino Acids* , 2005, Journal of Biological Chemistry.

[5]  D. Case,et al.  Theory and applications of the generalized born solvation model in macromolecular simulations , 2000, Biopolymers.

[6]  Tin Wee Tan,et al.  SDPMOD: an automated comparative modeling server for small disulfide-bonded proteins , 2004, Nucleic Acids Res..

[7]  Nick C. Polfer,et al.  Structure-Activity Relationships in Defensin Dimers , 2004, Journal of Biological Chemistry.

[8]  R D Kamm,et al.  Self-assembly of a beta-sheet protein governed by relief of electrostatic repulsion relative to van der Waals attraction. , 2000, Biomacromolecules.

[9]  Nir Ben-Tal,et al.  Increased concentration of polyvalent phospholipids in the adsorption domain of a charged protein. , 2003, Biophysical journal.

[10]  C. Hsiao,et al.  Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin , 2006, Journal of Biological Chemistry.

[11]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[12]  Andreas Hoenger,et al.  De novo designed peptide-based amyloid fibrils , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Bhyravabhotla Jayaram,et al.  Solvation Free Energy of Biomacromolecules: Parameters for a Modified Generalized Born Model Consistent with the AMBER Force Field , 1998 .

[14]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[15]  A. Waring,et al.  Solid-state NMR investigation of the depth of insertion of protegrin-1 in lipid bilayers using paramagnetic Mn2+. , 2003, Biophysical journal.

[16]  P. Savarin,et al.  Membrane Protein Insertion Regulated by Bringing Electrostatic and Hydrophobic Interactions into Play , 2002, The Journal of Biological Chemistry.

[17]  J. Thompson,et al.  The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. , 1997, Nucleic acids research.

[18]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[19]  Andreas Peschel,et al.  Chemokines Meet Defensins: the Merging Concepts of Chemoattractants and Antimicrobial Peptides in Host Defense , 2002, Infection and Immunity.

[20]  Y. Shai.  Molecular recognition between membrane-spanning polypeptides. , 1995, Trends in biochemical sciences.

[21]  H. Vogel,et al.  The Solution Structures of the Human β-Defensins Lead to a Better Understanding of the Potent Bactericidal Activity of HBD3 against Staphylococcus aureus * , 2002, The Journal of Biological Chemistry.

[22]  Robert Blumenthal,et al.  The Structure of Human β-Defensin-2 Shows Evidence of Higher Order Oligomerization* , 2000, The Journal of Biological Chemistry.

[23]  D. Eisenberg,et al.  Defensins promote fusion and lysis of negatively charged membranes , 1993, Protein science : a publication of the Protein Society.

[24]  Diana Murray,et al.  A computational model for the electrostatic sequestration of PI(4,5)P2 by membrane-adsorbed basic peptides. , 2004, Biophysical journal.

[25]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .

[26]  A. Pardi,et al.  NMR studies of defensin antimicrobial peptides. 1. Resonance assignment and secondary structure determination of rabbit NP-2 and human HNP-1. , 1992, Biochemistry.

[27]  D. Eisenberg,et al.  Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. , 1991, Science.

[28]  T. Ganz.  Defensins: antimicrobial peptides of innate immunity , 2003, Nature Reviews Immunology.

[29]  Nathan A. Baker,et al.  Electrostatics of nanosystems: Application to microtubules and the ribosome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[31]  K. Sharp,et al.  Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons , 1991, Proteins.

[32]  Frederic Rousseau,et al.  How evolutionary pressure against protein aggregation shaped chaperone specificity. , 2006, Journal of molecular biology.