Molecular dynamics simulations of helical antimicrobial peptides in SDS micelles: What do point mutations achieve?

Abstract

We have carried out a 40-ns all-atom molecular dynamics simulation of the helical antimicrobial peptide ovispirin-1 (OVIS) in a zwitterionic diphosphocholine (DPC) micelle. The DPC micelle serves as an economical and effective model for a cellular membrane owing to the presence of a choline headgroup, which resembles those of membrane phospholipids. OVIS, which was initially placed along a micelle diameter, diffuses out to the water-DPC interface, and the simulation stabilizes to an interface-bound steady state in 40 ns. The helical content of the peptide marginally increases in the process. The final conformation, orientation, and the structure of OVIS are in excellent agreement with the experimentally observed properties of the peptide in the presence of lipid bilayers composed of 75% zwitterionic lipids. The amphipathic peptide binds to the micelle with its hydrophobic face buried in the micellar core and the polar side chains protruding into the aqueous phase. There is overwhelming evidence that points to the significant and indispensable participation of hydrophobic residues in binding to the zwitterionic interface. The simulation starts with a conformation that is unbiased toward the final experimentally known binding state of the peptide. The ability of the model to reproduce experimental binding states despite this starting conformation is encouraging.

Molecular dynamics investigation of the influence of anionic and zwitterionic interfaces on antimicrobial peptides’ structure: Implications for peptide toxicity and activity

“…Although simulations of peptides in DPC [16,23,38] and SDS [1,4,24,25,40,41] micelles have been carried out in the past, the current study focuses on the larger context of secondary structure induction near membrane interfaces, and the remarkable influence this has on the toxicity of antimicrobial peptides. It is also one of the most computationally intensive studies that we are aware of, with more than 200 ns of combined molecular dynamics simulations.…”

“…The simulation was carried out using CHARMM Version c30b2 with the all atom param22 parameter set. We have shown earlier that unnatural π-helices are not formed with the param22 parameter sets in peptidemicelle simulation setups [23]. Because the equilibrium steady state was reached after 25 ns (see later), ensemble average properties were calculated for the last 14 ns of the simulation.…”

“…The simulations in SDS micelles were carried out as described in our previous work [23]. The only difference being that in the current work, the peptide was initially placed in the aqueous phase.…”

“…This allows much longer simulations and permits monitoring of biological phenomena of longer time scales. In our recent work, we have shown that the micelle model is successful in capturing experimentally observed binding states of small peptides [23,24]. DPC lipids carry a choline head group like zwitterionic phospholipids (DMPC, DPPC, etc.…”

“…For structure comparison purposes, simulations have also been carried out in anionic sodiumdodecylsulfate (SDS) micelles. We have previously reported simulations in SDS micelles [23,26]. In those simulations, the peptide was initially placed along a micelle diameter.…”