Ab initio free energy calculations of guanidinium pairing in aqueous solution confirm the counterintuitive conjecture that the like-charge ion pair is thermodynamically stable. Transferring the guanidinium pair to the inside of a POPC lipid bilayer, like-charge ion pairing is found to occur also inside the membrane defect. It is found to contribute to the nonadditivity of ion transfer, thereby facilitating the presence of ions inside the bilayer. The effect is quantified by free energy decomposition and comparison with ammonium ions, which do not form a stable pair. The presence of two charges inside the center of the bilayer leads to the formation of a pore. Potential consequences for cell penetrating peptides and ion conduction are drawn.

Department of Physics Tampere University of Technology P O Box 692 FI 33101 Tampere Finland

Institut für Physikalische and Theoretische Chemie Universität Regensburg 93040 Regensburg Germany

Institut Rudjer Bošković Bijenička cesta 54 10000 Zagreb Croatia

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nám 2 CZ 166 10 Prague 6 Czech Republic

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Molecular dynamics simulations unveil the aggregation patterns and salting out of polyarginines at zwitterionic POPC bilayers in solutions of various ionic strengths

Self-association of a highly charged arginine-rich cell-penetrating peptide