Orientational Nanoconjugation with Gold Endows Marked Antimicrobial Potential and Drugability of Ultrashort Dipeptides.

Antibiotic resistance is a global threat. Antimicrobial peptides (AMPs) are highly desirable to treat multidrug-resistant pathogen infection. However, few AMPs are clinically available, due to high cost, instability, and poor selectivity. Here, ultrashort AMPs (2-3 residues with an N-terminal cysteine) are designed and assembled as gold nanoparticles. Au-S conjugation and ultrashort size restrict nonspecific reactions and peptide orientation, thus concentrating positively charged residues on the surface. The nanostructured assemblies enormously enhance antimicrobial abilities by 1000-6000-fold and stability. One representative (Au-Cys-Arg-NH2, Au_CR) shows selective antibacterial activity against Staphylococcus aureus with 10 nM minimal inhibitory concentration. Au_CR has comparable or better in vivo antimicrobial potency than vancomycin and methicillin, with low propensity to induce resistance, little side effects, and high stability (17.5 h plasma half-life). Au_CR acts by inducing collapse of membrane potential and rupture of the bacterial membrane. The report provides insights for developing AMP-metal nanohybrids, particularly tethering nonspecific reactions and AMP orientation on the metal surface.

Thermodynamical Origin of Nonmonotonic Inserting Behavior of Imidazole Ionic Liquids into the Lipid Bilayer.

The GPU-accelerated molecular dynamics simulations are performed to explore the dynamical inserting process of ionic liquids (ILs) into the lipid bilayer. We found that the free ions and clusters coexist in the system, but only the cation can insert into the lipid bilayer. In specific, after a microsecond-scale simulation (up to 1.16 µs), the inserting rate increases first and then decreases nonmonotonic as side chain of cation (nchain) elongates, peaking at nchain = 10. However, the inserting free energy decreases with nchain, indicating the inserting process is easier for the larger nchain. Such contrary originates from the formation of cluster, where the cluster dissociating energy shows that only cluster for nchain ≤ 10 can dissociate spontaneously. Hence, the inserting rate is determined by the balance between nchain and cluster stability. These quantitative competition mechanisms shed light to the rational design of the biocompatible ILs toward their applications in the biochemical-related fields.