Influence of disulfide connectivity, electrostatics, and hydrophobicity on the conformational variations of alpha-conotoxin GI single-disulfide analogues: simulations with polarizable force field.

The roles of the disulfide bridge, electrostatics, and hydrophobic/hydrophilic effects in the structural stability and conformational changes of six single-disulfide analogues of alpha-conotoxin GI(2-7;3-13) in aqueous solution are investigated by using molecular dynamics simulations with a fragment-based polarization model (J. Phys. Chem. A 2008, 112, 9854.). It is found that the relative stabilities are largely determined by the dipole-dipole interactions between secondary structure-based fragments, revealing the favorable effect of polar residues on conformational stabilities. The loop size closely correlates to not only the thermodynamic stability but also the local geometry of disulfide bridge. The disulfide loops with no more than five residues [GI(2-7), GI(3-7), and GI(7-13)] choose the left-handed disulfide conformation, while the larger loops [with nine and 10 residues in GI(3-13) and GI(2-13)] and a smaller disulfide loop [GI(2-3) without intercysteine residue] prefer the right-handed configuration. In the left-handed analogues, the dihedral angles concerning disulfide bonds decrease subtly along with the enlargement of disulfide loops. A converse dihedral angle and loop size relationship is found in the right-handed isomers. These results are rationalized by the strain energy of the disulfide bond as well as the electrostatic and van der Waals interactions between cysteine pairs. The single-disulfide analogues also exhibit much higher conformational diversity than the native GI. The important role of the size of hydrophobic core in the conformational evolution is also demonstrated in terms of the radius of gyration of the hydrophobic region. The radial distribution functions show the significant solvent-solute hydrogen bonding, implying that the interplay between the intermolecular and the intramolecular interactions control the dynamic process of GI single-disulfide analogues.