Fig 1.
Structure of the siRNA sequence dGdG(AGCAGCACCUUCAGGAU)dUdU and the polycationic polymers investigated in the present work.
Fig 2.
Nucleotides that are mainly responsible for siRNA-polycation interaction have been identified by contact probability plots [71] in case of PEI27, PEI45, polyARG and polyLYS systems.
Fig 3.
Distribution plot of the Radius of Gyration (RG) of polyARG, polyLYS, PEI27 and PEI45, respectively.
The computational data were taken from the last 20 ns of the Replica Exchange Molecular Dynamics trajectory at 300K, for each molecular system.
Fig 4.
a) Radial distribution function (RDF) of polycation amine groups around O1P and O2P siRNA atoms for each molecular system reported in figure legend. Only charged amine groups are considered for the calculation. b) Average number of amine groups of each polycationic chain interacting with siRNA O1P and O2P atoms averaged over the last 20 ns of each Replica Exchange Molecular Dynamics trajectory at 300K. c) Radial distribution function (RDF) of polycation amine groups around electronegative atoms in siRNA grooves for each molecular system reported in figure legend. Only charged amine groups are considered for the calculation. The siRNA base edges that could participate in hydrogen bonds are N6 and N7 of adenine, O4 of uracil, O6 and N7 of guanine, and N4 of cytosine d) Average number of amine groups of each polycationic chain interacting with electronegative atoms in siRNA groves averaged over the last 20 ns of each Replica Exchange Molecular Dynamics trajectory at 300K.
Fig 5.
Free energy profile (kJ/mol) of siRNA-PEI27 interaction represented as function of siRNA-polycation distance from the major inertia axis of the target siRNA (distance from axis-DFA) and the projection of the siRNA-polymer distance on the major inertia axis of the target siRNA (projection on axis-POA).
The free energy minima computed by metadynamics are compared with the system configurations sampled by REMD simulations (black triangle). The deepest binding site is highlighted with BS1. The visual inspection of each binding site is reported together with the corresponding electrostatic map (right). Potential isocontours are shown at +5kT/e (blue) and -5kT/e (red) and obtained by solution of the LPBE at 150 mM ionic strength with a solute dielectric of 4 and a solvent dielectric of 78.4.
Fig 6.
Free energy profile (kJ/mol) of siRNA-PEI45 interaction represented as function of siRNA-polycation distance from the major inertia axis of the target siRNA (distance from axis-DFA) and the projection of the siRNA-polymer distance on the major inertia axis of the target siRNA (projection on axis-POA).
The free energy minima computed by metadynamics are compared with the system configurations sampled by REMD simulations (black trianle). The deepest binding site is highlighted with BS1. The visual inspection of each binding site is reported together with the corresponding electrostatic map (right). Potential isocontours are shown at +5kT/e (blue) and -5kT/e (red) and obtained by solution of the LPBE at 150 mM ionic strength with a solute dielectric of 4 and a solvent dielectric of 78.4.
Fig 7.
Free energy profile (kJ/mol) of siRNA-polyARG interaction represented as function of siRNA-polycation distance from the major inertia axis of the target siRNA (distance from axis-DFA) and the projection of the siRNA-polymer distance on the major inertia axis of the target siRNA (projection on axis-POA).
The free energy minima computed by metadynamics are compared with the system configurations sampled by REMD simulations (black triangle). The deepest binding site is highlighted with BS1. The visual inspection of each binding site is reported together with the corresponding electrostatic map (right). Potential isocontours are shown at +5kT/e (blue) and -5kT/e (red) and obtained by solution of the LPBE at 150 mM ionic strength with a solute dielectric of 4 and a solvent dielectric of 78.4.
Fig 8.
Free energy profile (kJ/mol) of siRNA-polyLYS interaction represented as function of siRNA-polycation distance from the major inertia axis of the target siRNA (distance from axis-DFA) and the projection of the siRNA-polymer distance on the major inertia axis of the target siRNA (projection on axis-POA).
The free energy minima computed by metadynamics are compared with the system configurations sampled by REMD simulations (black triangle). The deepest binding site is highlighted with BS1. The visual inspection of each binding site is reported together with the corresponding electrostatic map (right). Potential isocontours are shown at +5kT/e (blue) and -5kT/e (red) and obtained by solution of the LPBE at 150 mM ionic strength with a solute dielectric of 4 and a solvent dielectric of 78.4.