Aggregation of methacrylate-based ternary biomimetic antimicrobial polymers in solution

Abstract

Using detailed atomistic simulations, we explore the morphological characteristics of aggregates formed in solution phase by ternary biomimetic antimicrobial (AM) methacrylate polymers, composed of hydrophobic, charged cationic and polar functional groups and compare it with aggregate morphologies of binary methacrylate polymers, composed only of hydrophobic and charged cationic functional groups. The effect of sequence of the constituent functional groups on aggregate conformation is also studied by considering random and block sequences along the polymer backbone. Our results show that while binary polymers tend to form robust aggregates, replacing some of the hydrophobic groups with overall charge neutral polar groups weakens the aggregate considerably, leading to increased conformational fluctuations and formation of loose-packed, open aggregates, particularly in the case of random ternary polymers. Interaction energy calculations clearly suggest that the role of inclusion of polar groups in ternary polymers is two-fold: (1) to reduce possible strong local concentration of hydrophobic groups and ‘smear’ the overall hydrophobicity along the polymer backbone to increase the solubility of the polymers (2) to compensate the loss of attractive hydrophobic interactions by forming attractive electrostatic interactions with the charged groups and contribute to aggregation formation, albeit weak. Given that most of the naturally occurring AM peptides have contributions from all the three functional groups, this study elucidates the functionally tuneable role of inclusion of polar groups in the way AM agents interact with each other in solution phase, which can eventually dictate their partitioning behaviour into bacterial and mammalian membranes.

Design of Antimicrobial Polymers

“…Inspired by these studies, our group has recently conducted a systemic investigation of the effect of hydrophilic groups on antibacterial activity and biocompatibility of statistical amphiphilic ternary polymers. [ 107 ] In agreement with the previous finding of Rani [ 115,116 ] and others, [ 109 ] we found that unlike hydrophobic groups that directly disrupt the cell membrane hydrophilic groups have an indirect but important impact on bioactivity through tuning of the hydrophobic/hydrophilic balance and global hydrophobicity, leading to a change in the aqueous characteristics of polymers. Therefore, in antimicrobial polymer design, an appropriate hydrophobic/hydrophilic balance as well as the structural features of the hydrophilic group, such as length, flexibility, and hydrophilicity of the hydrophilic chain, are key determinants that can be optimized to enhance the AMP selectivity toward pathogens over host cells.…”

Role of lipid packing defects in determining membrane interactions of antimicrobial polymers

“…Both ternary and binary polymers have a degree of polymerisation (DP) = 19 with the groups in a random sequence with a composition of 6 AEMA units, 8 EMA units, 5 HEMA units for model T polymers and 6 AEMA units, 13 EMA units for model B polymers. For further details and an in depth study of such polymers and their conformations in solution and membrane phase we refer to our previous works [17, 18]. The bacterial membrane consists of 38 POPG and 90 POPE lipid molecules per leaflet to mimic the inner membrane of the Gram negative bacteria [29].…”

“…The AEMA units, 13 EMA units for model B polymers. For further details and an in depth study of such polymers and their conformations in solution and membrane phase we refer to our previous works [17,18]. The bacterial membrane consists of 38 POPG and 90 POPE lipid molecules per leaflet to mimic the inner mem-module [30] was used to construct the the membrane system, similar to our previous works [31,32,18].…”

“…It is important to understand how differently they interact with bacterial membranes when compared to the previously described binary composition in designing better antimicrobial mimics. Recently we showed that replacing some of the hydrophobic groups in a binary biomimetic polymer with polar groups significantly alters how the resultant ternary polymers interact in solution phase and with bacterial membranes[17, 18]. The studies also strongly suggest that the inclusion of polar groups smears the overall hydrophobicity of such polymers and result in a globular conformations when partitioned into the bacterial membrane, likely mimic of defensin-like antimicrobial peptides [19, 20].…”

Role of Lipid Packing Defects in Determining Membrane Interactions of Antimicrobial Polymers

“…It is important to understand how differently they interact with bacterial membranes when compared to the previously described binary composition in designing better antimicrobial mimics. Recently we showed that replacing some of the hydrophobic groups in a binary biomimetic polymer with polar groups significantly alters how the resultant ternary polymers interact in solution phase and with bacterial membranes. , The studies also strongly suggest that the inclusion of polar groups smears the overall hydrophobicity of such polymers and result in a globular conformations when partitioned into the bacterial membrane, likely mimic of defensin-like antimicrobial peptides. , …”