engleski

Correlation Of Membrane Interaction Simulations With Experimental Effects For Kiadin Antimicrobial Peptides

Kiadins are linear, glycine- and lysine-rich peptides, in silico designed based either on a template derived from the tandem-repeat of the small natural peptide PGLa-H, or on a de novo approach using quantitative structure–activity relationship models [1, 2]. They showed a quite variable activity against Gram-positive and -negative bacterial pathogens, including drug resistant strains, as well as a variable cyto/ genotoxicity when tested on human blood cells. Atomic force microscopy confirmed that they act through membrane damage, leading to its permeabilization, as also confirmed by flow cytometry, but with subtly different modes of action. An initial molecular dynamics (MD) study provided some insight into this mechanism, suggesting the peptides have different interacting preferences with a model biological membrane. Activity and selectivity appear to be influenced in particular by the number and placing of glycine residues along the sequence [2]. We then took into consideration the possibility that the manner in which a peptide faces the membrane surface on its approach could affect the initial mode of action, and subsequently also affect how it inserts into the lipid layer, eventually disrupting it. We relate these in silico results to the strength of interaction with an immobilized liposomes having a membrane composed of the same phospholipids, using surface plasmon resonance. In particular, we attempted to understand why a higher proportion of Gly residues in the sequence correlated with a reduced antibacterial potency but did not necessarily result in a lower toxicity towards host cells. [1] T. Rončević, G. Gajski, N. Ilić, I. Goić-Barišić, M. Tonkić, L. Zoranić, J. Simunić, M. Benincasa, M. Mijaković, A. Tossi, D. Juretić, Biochim. Biophys. Acta BBA - Biomembr. 1859 (2017) 228–237. doi:10.1016/j.bbamem. 2016.11.011 ; [2] T. Rončević, D. Vukičević, N. Ilić, L. Krce, G. Gajski, M. Tonkić, I. Goić-Barišić, L. Zoranić, Y. Sonavane, M. Benincasa, D. Juretić, A. Maravić, A. Tossi, J. Med. Chem. 61 (2018) 2924–2936. doi:10.1021/acs. jmedchem.7b01831.

Interakcija s membranom ; simulacije molekulske dinamike

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