A molecular dynamics and circular dichroism study of a novel synthetic antimicrobial peptide

Antimicrobial peptides are a class of small, usually positively charged amphiphilic peptides that are used by the innate immune system to combat bacterial infection in multicellular eukaryotes. Antimicrobial peptides are known for their broad-spectrum antimicrobial activity and thus can be used as a basis for a development of new antibiotics against multidrug-resistant bacteria. The most challengeous task on the way to a therapeutic use of antimicrobial peptides is a rational design of new peptides with enhanced activity and reduced toxicity. Here we report a molecular dynamics and circular dichroism study of a novel synthetic antimicrobial peptide D51. This peptide was earlier designed by Loose et al. using a linguistic model of natural antimicrobial peptides. Molecular dynamics simulation of the peptide folding in explicit solvent shows fast formation of two antiparallel beta strands connected by a beta-turn that is confirmed by circular dichroism measurements. Obtained from simulation amphipatic conformation of the peptide is analysed and possible mechanism of it's interaction with bacterial membranes together with ways to enhance it's antibacterial activity are suggested. 1. Introduction Antimicrobial peptides (AMPs) are generally defined as short peptides of less than 50 residues with overall positive charge and substantial portion of hydrophobic residues. Natural antimicrobial peptides found in different multicellular eukaryotes and are an important part of the innate immune system that defend host organism against pathogenic microbes[1]. Broad-spectrum activity of antimicrobial peptides against multidrug-resistant bacteria make them potential next-generation antibiotics[2]. Currently more than 2000 AMP sequences can be found in Antimicrobial Peptide Database[3]. Most of the studied antimicrobial peptides with known structure belong to three major structural classes: α-helix, β-sheet or combined α+β-structures. Spatial structure (conformation) of a peptide molecule defines a specific distribution of physico-chemical properties such as an electric charge and hydrophobicity on a molecular surface. Presence of a certain amphipatic conformation is essential for an antimicrobial activity of a peptide. It is widely accepted that antimicrobial peptides target the lipid bilayer of the bacterial cell membrane, and their selectivity is based on higher electrostatic affinity of cationic peptides to negatively charged bacterial membranes than to electrically neutral lipids forming membranes of mammalian cells[4]. Most of the natural antimicrobial peptides are not enough active to be used as therapeutic agents straightforwardly. Thus, new design approaches are required to build synthetic antimicrobial peptides with enhanced activity. Among other modern methods of peptide design