The potential energy surface of four stereoselective Diels-Alder reactions was studied, namely: cyclopentadiene-maleic anhydride, furan-maleic anhydride, the dimerization of cyclopentadiene, and cyclopentadiene-cyclopropene. For completeness, we also studied the reaction between ethylene and 2-hydroxy-6-methyl-1,4-benzoquinone, a [5+2] cycloaddition reaction. For all cases at least a stationary state of supramolecular nature a van der Waals complex, was determined. These stationary states are complexes formed by the interaction between the reagents, minima located in the paths between the non-interacting molecules and the transition states. The existence of these complexes makes it necessary to reconsider the role of Secondary Orbital Interactions in the selectivity of these reactions. As it is the case with other complexes, the stability of these supramolecular intermediates depends on electrostatic phenomena such as dispersion forces. The observation of [5+2] intramolecular complexes in solution is important since up to now, this kind of van der Waals complexes had only been described in the gas phase.

Rational design of peptide vaccines becomes important for the treatment of some diseases such as Alzheimer’s disease (AD) and related disorders. In this study, as part of a larger effort to explore correlations of structure and activity, we attempt to characterize the doubly phosphorylated chimeric peptide vaccine targeting a hyperphosphorylated epitope of the Tau protein. The 28-mer linear chimeric peptide consists of the double phosphorylated B cell epitope Tau_229-237[pThr231/pSer235] and the immunomodulatory T cell epitope Ag85B_241-255 originating from the well-known antigen Ag85B of the Mycobacterium tuberculosis, linked by a four amino acid sequence -GPSL-. NMR chemical shift analysis of our construct demonstrated that the synthesized peptide is essentially unfolded with a tendency to form a β-turn due to the linker. In conclusion, the -GPSL- unit presumably connects the two parts of the vaccine without transferring any structural information from one part to the other. Therefore, the double phosphorylated epitope of the Tau peptide is flexible and accessible.