How Melittin Inserts into Cell Membrane: Conformational Changes, Inter-Peptide Cooperation, and Disturbance on the Membrane

Abstract

Antimicrobial peptides (AMPs), as a key component of the immune defense systems of organisms, are a promising solution to the serious threat of drug-resistant bacteria to public health. As one of the most representative and extensively studied AMPs, melittin has exceptional broad-spectrum activities against microorganisms, including both Gram-positive and Gram-negative bacteria. Unfortunately, the action mechanism of melittin with bacterial membranes, especially the underlying physics of peptide-induced membrane poration behaviors, is still poorly understood, which hampers efforts to develop melittin-based drugs or agents for clinical applications. In this mini-review, we focus on recent advances with respect to the membrane insertion behavior of melittin mostly from a computational aspect. Membrane insertion is a prerequisite and key step for forming transmembrane pores and bacterial killing by melittin, whose occurrence is based on overcoming a high free-energy barrier during the transition of melittin molecules from a membrane surface-binding state to a transmembrane-inserting state. Here, intriguing simulation results on such transition are highlighted from both kinetic and thermodynamic aspects. The conformational changes and inter-peptide cooperation of melittin molecules, as well as melittin-induced disturbances to membrane structure, such as deformation and lipid extraction, are regarded as key factors influencing the insertion of peptides into membranes. The associated intermediate states in peptide conformations, lipid arrangements, membrane structure, and mechanical properties during this process are specifically discussed. Finally, potential strategies for enhancing the poration ability and improving the antimicrobial performance of AMPs are included as well.

Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests

“…The use of apitoxin, especially its main compound melittin, as a novel cancer-treatment strategy has gained wide importance recently [70,71]. In fact, melittin is known to be a nonspecific cytolytic peptide that can attack the lipid bilayer, thus leading to a significant toxicity when injected intravenously [72]. Nevertheless, many optimization approaches, including the use of nanoparticle-based delivery of melittin, have been exploited.…”

“…Nevertheless, many optimization approaches, including the use of nanoparticle-based delivery of melittin, have been exploited. Remarkably, the crude BV as well as melittin have shown antitumor activities against different cancer cell types including breast, liver, leukemia, lung, melanoma, and prostate cancer cells [70,72,73,74,75]. Wang et al [76] investigated the mechanism behind melittin antitumor activity and showed that melittin can induce apoptosis of hepatocellular carcinoma cells (HCC) through the activation of the CAMKII-TAK1-JNK/p38 signaling pathway (CAMKII: Ca 2+ /calmodulin-dependent protein kinase; TAK1: Transforming growth factor-beta-activated kinase 1; JNK/p38: Mitogen-activated protein kinases).…”

Bee venom inhibits the proliferation and migration of cervical-cancer cells in an HPV E6/E7-dependent manner

“…Recent studies have shown that the main peptide component of BV, melittin, has an anti-cancer effect (12,13). Melitin is a non-specific cytolytic peptide that can break down lipid bilayers and is toxic when injected (14). However, via an optimized nanoparticle-based approach, it exhibits anti-cancer effects on several cancer cells, including leukemia, liver cancer, lung cancer, and prostate cancer cells (15).…”

Ferritin Nanocages for Protein Delivery to Tumor Cells

“…Many plant toxins, including saporin and ricin, are ribosome-inactivating proteins [4]. Animal toxins display an array of cytotoxic activity, ranging from membranolysis (melittin from Apis mellifera) [5] to chloride channels blocking (chlorotoxin from Leiurus quinquestriatus) [6]. Antimicrobial peptides, some of them known as anticancer peptides, promote cell lysis through pore formations [7].…”