From Molecular Insight to Mesoscale Membrane Remodeling: Curvature Generation by Arginine‐Rich Cell‐Penetrating Peptides

The enhanced cell penetration ability of arginine-rich peptides, such as nonaarginine ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>R</mml:mi> <mml:mn>9</mml:mn></mml:msub> <mml:annotation>${\rm R}_9$</mml:annotation></mml:semantics> </mml:math> ), compared to their lysine-rich counterparts, remains incompletely understood. Atomistic simulations reveal that <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>R</mml:mi> <mml:mn>9</mml:mn></mml:msub> <mml:annotation>${\rm R}_9$</mml:annotation></mml:semantics> </mml:math> binds significantly stronger ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mo>≈</mml:mo> <mml:mn>20</mml:mn> <mml:mspace></mml:mspace> <mml:mi>kJ</mml:mi> <mml:mo>/</mml:mo> <mml:mi>mol</mml:mi></mml:mrow> <mml:annotation>$\approx 20\nobreakspace \mathrm{kJ/mol}$</mml:annotation></mml:semantics> </mml:math> ) and penetrates deeper into the anionic lipid headgroup region than its lysine equivalent. This enhanced interaction translates into a stronger induction of negative membrane curvature by <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>R</mml:mi> <mml:mn>9</mml:mn></mml:msub> <mml:annotation>${\rm R}_9$</mml:annotation></mml:semantics> </mml:math> . We introduce an integrative modeling workflow to extract and incorporate material properties from molecular simulations into a continuum membrane model that includes peptide binding and curvature induction. Our model predicts that stable membrane invaginations, as observed in studies of cell penetration, require excess membrane and are stable only for <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>R</mml:mi> <mml:mn>9</mml:mn></mml:msub> <mml:annotation>${\rm R}_9$</mml:annotation></mml:semantics> </mml:math> . By analyzing lipid and protein sorting coupled to the membrane structure, we explain the interplay of Gaussian and mean curvature in providing a mechanistic basis for the initial membrane deformation events potentially involved in "Arginine Magic" cell entry pathways.