Non-covalent interactions

Non-covalent interactions play an important part in determining the stability of biological macromolecules. Disruption of these interactions can significantly alter the energetics of a polypeptide chain.

The following images show the cyclic octapeptide Patellamide C from Lissoclinum patella, a species of ascidian or 'sea-squirt'. The first image is a conformation modelled using the MM2* force field including nOe distance restraints from an NMR experiment and the second is the global minimum energy conformation generated from an unrestrained Monte-Carlo simulation, again using the MM2* force field. The force field geometries were then re-optimised at the DFT/B3LYP/6-31G(d,p) level.

The volume data plotted in these images comes from the NCIPlot software program [1] and is the reduced density gradient (RDG)

    \[ 	s(\mathbf{r}) = \frac{1}{2(3\pi^2)^{1/3}} \frac{\left|\nabla\rho(\mathbf{r})\right|}{\rho(\mathbf{r})^{4/3}} 	\]

Each point on the surfaces coloured by the value of the second eigenvalue \lambda_2 of the Hessian of the Laplacian of the charge density \nabla^2\rho(\mathbf{r}) at that point. This combination provides information on regions where non-covalent closed-shell interactions occur. The colour scheme used corresponds to strong stabilising interactions (blue), weak Van der Waals type interactions (green) and strongly repulsive interactions (red).

NMR structure

Patellamide C modelled structure

Unrestrained global minimum structure


Strong repulsive interactions can be seen at the center of phenyl, thiazole and oxazole rings but overall most of the interactions are of the VdW type and are weakly stabilising. Discs/ovals of blue density can be seen in positions where hydrogen bonding occurs in the unrestrained second structure but this feature is largely missing from the more open NMR structure indicating less stabilisation of by H-bonds. Similarly, the opening up of the patellamide C structure in the NMR model leads to significant loss of VdW surfaces which would also be expected to destabilise the molecule.

Inspection of the RDG surfaces would suggest that the global minimum structure should be significantly more stabilised by non-covalent interactions than the NMR structure and comparison of the two structures' energies confirms this. At the B3LYP/6-31G(d,p) level, including VdW corrections, the NMR structure is found to be 130 kJ/mol higher in energy than the unrestrained structure. This value corresponds to the gas phase, however it is unlikely that solvent effects would reverse this situation and such a large energy difference suggests essentially zero population of the NMR-derived structure at 300 K.

[1] Contreras-García et al, J. Chem. Theory Comput.20117 (3), pp 625–632