Marine cone snails belonging to the Conidae family make use of neuroactive peptides in their venom to capture prey. Here we report the proteome profile of the venom duct of Conus eburneus, a cone snail belonging to the Tesseliconus clade. Through tandem mass spectrometry and database searching against the C. eburneus transcriptome and the ConoServer database, we identified 24 unique conopeptide sequences in the venom duct. The majority of these peptides belong to the T and M gene superfamilies and are disulfide-bonded, with cysteine frameworks V, XIV, VI/VII, and III being the most abundant. All seven of the Cys-free peptides are conomarphin variants belonging to the M superfamily that eluted out as dominant peaks in the chromatogram. These conomarphins vary not only in amino acid residues in select positions along the backbone but also have one or more post-translational modifications (PTMs) such as proline hydroxylation, C-term amidation, and γ-carboxylation of glutamic acid. Using molecular dynamics simulations, the conomarphin variants were predicted to predominantly have hairpin-like or elongated structures in acidic pH. These two structures were found to have significant differences in electrostatic properties and the inclusion of PTMs seems to complement this disparity. The presence of polar PTMs (hydroxyproline and γ-carboxyglutamic acid) also appear to stabilize hydrogen bond networks in these conformations. Furthermore, these predicted structures are pH sensitive, becoming more spherical and compact at higher pH. The subtle conformational variations observed here might play an important role in the selection and binding of the peptides to their molecular targets.

Cupiennin 1a is an antimicrobial peptide found in the venom of the spider Cupiennius salei. A highly cationic peptide, its cell lysis activity has been found to vary between neutral and charged membranes. In this study, Hamiltonian replica-exchange molecular dynamics (HREMD) was used to determine the conformational ensemble of the peptide in both charged (pH 3) and neutral (pH 11) states. The obtained free energy landscapes demonstrated the conformational diversity of the neutral peptide. At high pH, the peptide was found to adopt helix–hinge–helix and disordered structures. At pH 3, the peptide is structured with a high propensity toward α-helices. The presence of these α-helices seems to assist the peptide in recognizing membrane surfaces. These results highlight the importance of the charged residues in the stabilization of the peptide structure and the subsequent effects of pH on the peptide’s conformational diversity and membrane activity. These findings may provide insights into the antimicrobial activity of Cupiennin 1a and other amphipathic linear peptides toward different cell membranes.

Emerging from Wuhan, China in December 2019, the SARS-CoV-2 virus has spread rapidly, prompting an immediate international response to contain the disease. In this paper, the most abundant volatile compounds in household aromatherapy ointments, namely, methyl salicylate, eucalyptol, α-pinene, menthol, camphor, linalool, and trans-pinocarveol were docked to key structures in SARS-CoV-2 invasion: its spike protein, and the human ACE2 and TMPRSS2 proteins. Based on the molecular docking results, the essential oil compounds methyl salicylate, eucalyptol, and α-pinene exhibit favorable binding to ACE2 and spike proteins. These compounds may be considered for clinical investigation.

AI-based protein design can rapidly generate thousands of candidate binders, but most fail to fold or bind productively, creating a critical need for robust prioritization.