In silico vaccine design based on molecular simulations of rhinovirus chimeras presenting HIV-1 gp41 epitopes

A cluster of promising epitopes for the development of HIV vaccines is located in the membrane-proximal external region (MPER) of the gp41 subunit of the HIV envelope spike structure. The crystal structure of the peptide corresponding to the so-called ELDKWA epitope (HIV-1 HxB2 gp41 residues 662–668) in complex with the corresponding broadly neutralizing human monoclonal antibody 2F5 provides a target for structure-based vaccine design strategies aimed at finding macromolecular carriers able to present this MPER-derived epitope with optimal antigenic activity. To this end, a series of replica exchange molecular dynamics computer simulations was conducted to characterize the distributions of conformations of ELDKWA-based epitopes inserted on a rhinovirus carrier and to identify those with the highest fraction of conformations able to bind 2F5. The length, the hydrophobic character, and the precise site of insertion were found to be critical for achieving structural similarity to the target crystal structure. A construct was obtained with a high degree of complementarity to the corresponding determinant region of 2F5. This construct was employed to build a high-resolution structural model of the complex between the 2F5 antibody and the chimeric HRV14:HIV-1 ELDKWA virus particle. Additional simulations, conducted to study the conformational propensities of the ELDKWA region in solution, confirm the hypothesis that the ELDKWA region of gp41 is highly flexible and capable of assuming helical conformations, as in the post-fusion helical bundle structure, as well as β-turn conformations, as in the complex with the 2F5 antibody. These results also suggest that the ELDKWA epitope can be involved in intramolecular and likely intermolecular hydrophobic interactions. This tendency offers an explanation for the observation that mutations decreasing the hydrophobic character of the MPER in many cases result in conformational changes that increase the affinity of this region for the 2F5 antibody.