title: Antimicrobial Peptide Simulations and the Influence of Force Field on the Free Energy for Pore Formation in Lipid Bilayers.
abstract: Due to antimicrobial resistance, the development of new drugs to combat bacterial and fungal infections is an important area of research. Nature uses short, charged, and amphipathic peptides for antimicrobial defense, many of which disrupt the lipid membrane in addition to other possible targets inside the cell. Computer simulations have revealed atomistic details for the interactions of antimicrobial peptides and cell-penetrating peptides with lipid bilayers. Strong interactions between the polar interface and the charged peptides can induce bilayer deformations - including membrane rupture and peptide stabilization of a hydrophilic pore. Here, we performed microsecond-long simulations of the antimicrobial peptide CM15 in a POPC bilayer expecting to observe pore formation (based on previous molecular dynamics simulations). We show that caution is needed when interpreting results of equilibrium peptide-membrane simulations, given the length of time single trajectories can dwell in local energy minima for 100's of ns to microseconds. While we did record significant membrane perturbations from the CM15 peptide, pores were not observed. We explain this discrepancy by computing the free energy for pore formation with different force fields. Our results show a large difference in the free energy barrier (ca. 40 kJ/mol) against pore formation predicted by the different force fields that would result in orders of magnitude differences in the simulation time required to observe spontaneous pore formation. This explains why previous simulations using the Berger lipid parameters reported pores induced by charged peptides, while with CHARMM based models pores were not observed in our long time-scale simulations. We reconcile some of the differences in the distance dependent free energies by shifting the free energy profiles to account for thickness differences between force fields. The shifted curves show that all the models describe small defects in lipid bilayers in a consistent manner, suggesting a common physical basis.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors.forename: W F Drew
authors.initials: WF
authors.lastname: Bennett
authors.affiliation: Shenzhen Research Institute, Chinese University of Hong Kong , Nanshan District, Shenzhen 518057, P. R. China.|Department of Physics, Chinese University of Hong Kong , Shatin, N.T., Hong Kong.
authors.forename: Chun Kit
authors.initials: CK
authors.lastname: Hong
authors.affiliation: Shenzhen Research Institute, Chinese University of Hong Kong , Nanshan District, Shenzhen 518057, P. R. China.|Department of Physics, Chinese University of Hong Kong , Shatin, N.T., Hong Kong.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary , Calgary, Alberta T2N1N4, Canada.
authors.forename: D Peter
authors.initials: DP
authors.lastname: Tieleman
mesh_terms: D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010539:Permeability / Q000187:drug effects; D010713:Phosphatidylcholines / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; C513873:antimicrobial hybrid peptide CM15; D014867:Water; C028694:1-palmitoyl-2-oleoylphosphatidylcholine