Article (Scientific journals)
Modeling of non-covalent complexes of the cell-penetrating peptide CADY and its siRNA cargo.
Crowet, Jean-Marc; Lins, Laurence; Deshayes, Sebastien et al.
2012In Biochimica et Biophysica Acta
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Abstract :
[en] CADY is a cell-penetrating peptide spontaneously making non-covalent complexes with siRNAs in water. Neither the structure of CADY nor that of the complexes is resolved. We have calculated and analyzed 3D models of CADY and of the non-covalent CADY-siRNA complexes in order to understand their formation and stabilization. Data from the ab initio calculations and molecular dynamics support that, in agreement with the experimental data, CADY is a polymorphic peptide partly helical. Taking into consideration the polymorphism of CADY, we calculated and compared several complexes with peptide/siRNA ratios of up to 40. Four complexes were run by using molecular dynamics. The initial binding of CADYs is essentially due to the electrostatic interactions of the arginines with siRNA phosphates. Due to a repetitive arginine motif (XLWR(K)) in CADY and to the numerous phosphate moieties in the siRNA, CADYs can adopt multiple positions at the siRNA surface leading to numerous possibilities of complexes. Nevertheless, several complex properties are common: an average of 14+/-1 CADYs is required to saturate a siRNA as compared to the 12+/-2 CADYs experimentally described. The 40 CADYs/siRNA that is the optimal ratio for vector stability always corresponds to two layers of CADYs per siRNA. When siRNA is covered by the first layer of CADYs, the peptides still bind despite the electrostatic repulsion. The peptide cage is stabilized by hydrophobic CADY-CADY contacts thanks to CADY polymorphism. The analysis demonstrates that the hydrophobicity, the presence of several positive charges and the disorder of CADY are mandatory to make stable the CADY-siRNA complexes.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Crowet, Jean-Marc ;  Université de Liège - ULiège > Chimie et bio-industries > Biophysique moléc. numér.
Lins, Laurence  ;  Université de Liège - ULiège > Chimie et bio-industries > Biophysique moléc. numér.
Deshayes, Sebastien
Divita, Gilles
Morris, May
Brasseur, Robert ;  Université de Liège - ULiège > Chimie et bio-industries > Biophysique moléc. numér.
Thomas, Annick ;  Université de Liège - ULiège > Chimie et bio-industries > Biophysique moléc. numér.
Language :
English
Title :
Modeling of non-covalent complexes of the cell-penetrating peptide CADY and its siRNA cargo.
Publication date :
2012
Journal title :
Biochimica et Biophysica Acta
ISSN :
0006-3002
eISSN :
1878-2434
Publisher :
Elsevier, Amsterdam, Netherlands
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2012 Elsevier B.V. All rights reserved.
Available on ORBi :
since 26 November 2012

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