Molecular dynamics study of the helix-to-disorder transition in short antimicrobial peptides from Urodacus yaschenkoi

The bioactivity of the short antimicrobial peptides (ssAMPs) UyCT1, CT2, CT3, CT5, Uy17, Uy192, and Uy234 from the scorpion Urodacus yaschenkoi has been well-characterized. The antagonistic effect reported in those studies on some clinical isolates of pathogenic bacteria, including Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli was studied with an in silico approach to contrast their bioactivity in molecular terms. The peptides were modeled by generating high-quality structures with AlphaFold2, properly validated, and subjected to dynamic simulations in aqueous systems with the Gromos 43a1 and Charmm 36 force fields. Our analysis indicates that the degree of helicity of these peptides is closely linked to their composition and several physicochemical factors such as the hydrophobicity index, electrostatic potential, intrinsic flexibility, and dipole moment. We also found interesting parallels between the degree of order mentioned and the potency of each peptide with previously studied bacterial strains, specifically S. aureus. We analyzed in more detail of two specific peptides, UyCT1 and UyCT2, whose sequences are almost identical, except for the presence of a G-cap in the former. This subtle difference has a decisive impact on the conformational dynamics of these peptides, making the UyCT2 peptide more prone to disorder and the UyCT1 peptide more stable through the formation of multiple H-bonds. This analysis, based on an exhaustive characterization of the physicochemical properties of these ssAMPs, together with the determination of their conformational dynamics and the correlation with experimental data, could be the basis for the design and optimization of new drugs based on natural peptides found in scorpion venoms.