Folding Molecular Dynamics Simulation of a gp41-Derived Peptide Reconcile Divergent Structure Determinations

[Image: see text] T-20 peptide is the first FDA-approved fusion inhibitor against AIDS/HIV-1 gp41 protein. Part of it, the gp41[659–671] peptide, that contains the complete epitope for the neutralizing 2F5 monoclonal antibody, has been found experimentally in a number of divergent structures. Herein, we attempt to reconcile them by using unbiased large-scale all-atom molecular dynamics folding simulations. We show that our approach can successfully capture the peptide’s heterogeneity and reach each and every experimentally determined conformation in sub-angstrom accuracy, whilst preserving the peptide’s disordered nature. Our analysis also unveils that the minor refinements within the AMBER99SB family of force fields can lead to appreciable differences in the predicted conformational stability arising from subtle differences in the helical- and β-region of the Ramachandran plot. Our work underlines the contribution of molecular dynamics simulation in structurally characterizing pharmacologically important peptides of ambiguous structure.