In Silico Structural Evaluation of Short Cationic Antimicrobial Peptides

Abstract

Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria. Two sets of cationic peptides (AMPs) with known antimicrobial activity have been investigated. The first reference set comprised molecules with experimentally-known conformations available in the protein databank (PDB), and the second one was composed of short peptides active against Gram negative bacteria but with no significant structural information available. The predicted structures of the peptides from the first set were in excellent agreement with those experimentally-observed, which allowed analysis of the structural features of the second group using computationally-derived conformations. The peptide conformations, either experimentally available or predicted, were clustered in an “all vs. all” fashion and the most populated clusters were then analyzed. It was confirmed that these peptides tend to assume an amphipathic conformation regardless of the environment. It was also observed that positively-charged amino acid residues can often be found next to aromatic residues. Finally, a protocol was evaluated for the investigation of the behavior of short cationic peptides in the presence of a membrane-like environment such as dodecylphosphocholine (DPC) micelles. The results presented herein introduce a promising approach to inform the design of novel short peptides with a potential antimicrobial activity.

Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli

“…Restoring the potency of antibiotics that are no longer in clinical use due to lack of efficacy or bacterial resistance is one potential route to extend the life of current therapies. Cationic antimicrobial peptides (AMPs) are found widely in nature and have been of interest as novel therapeutics [1][2][3]. AMPs are believed to act via interaction with bacterial membranes, leading to increased cell permeability or membrane disruption.…”

“…Around 5000 AMPs have been reported, with ca. 1000 having a published structure [1]. Our previous investigation of the sequences and conformations of a library of cationic antimicrobial peptide structures highlighted the importance of alternating basic and aromatic amino acid residues [1].…”

“…1000 having a published structure [1]. Our previous investigation of the sequences and conformations of a library of cationic antimicrobial peptide structures highlighted the importance of alternating basic and aromatic amino acid residues [1]. This is thought to be important in allowing the peptides to assume the amphipathic conformation that is required for them to interact with the bacterial membrane.…”

Deep Learning for Novel Antimicrobial Peptide Design

“…Additionally, 3D structures and surfaces of the newly generated AMPs showed similarities with typical AMP amphipathic short alpha-helix structures [ 10 , 11 ]. However, some of the generated structures lacked an amphipathic character or alpha-helical structure, despite being classified as antimicrobial by the models.…”

“…AMPs are naturally present in the innate immune system and have broad-spectrum antimicrobial properties aiding in the defence against invading microorganisms [ 8 , 9 ]. They are usually short cationic peptides of up to 100 amino acids [ 9 ], that often adopt an alpha-helical secondary structure with amphiphilic surface properties, regarded as essential for establishing antimicrobial activity [ 10 , 11 , 12 ]. AMPs’ main mechanism of action is the disruption of the target microorganism’s cell membrane, through hydrophobic or electrostatic interactions, causing lysis of the cell [ 13 ].…”