Incorporation of antimicrobial peptides into membranes: a combined liquid-state NMR and molecular dynamics study of alamethicin in DMPC/DHPC bicelles.
Detailed insight into the interplay between antimicrobial peptides and biological membranes is fundamental to our understanding of the mechanism of bacterial ion channels and the action of these in biological host-defense systems. To explore this interplay, we have studied the incorporation, membrane-bound structure, and conformation of the antimicrobial peptide alamethicin in lipid bilayers using a combination of 1H liquid-state NMR spectroscopy and molecular dynamics (MD) simulations. On the basis of experimental NMR data, we evaluate simple in-plane and transmembrane incorporation models as well as pore formation for alamethicin in DMPC/DHPC (1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine/1,2-dihexanoyl-sn-glycero-3-phosphatidylcholine) bicelles. Peptide-lipid nuclear Overhauser effect (NOE) and paramagnetic relaxation enhancement (PRE) data support a transmembrane configuration of the peptide in the bilayers, but they also reveal that the system cannot be described by a single simple conformational model because there is a very high degree of dynamics and heterogeneity in the three-component system. To explore the origin of this heterogeneity and dynamics, we have compared the NOE and PRE data with MD simulations of an ensemble of alamethicin peptides in a DMPC bilayer. From all-atom MD simulations, the contacts between peptide, lipid, and water protons are quantified over a time interval up to 95 ns. The MD simulations provide a statistical base that reflects our NMR data and even can explain some initially surprising NMR results concerning specific interactions between alamethicin and the lipids.
Dittmer
Jens
J
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry, University of Aarhus, Denmark.
Thøgersen
Lea
L
Underhaug
Jarl
J
Bertelsen
Kresten
K
Vosegaard
Thomas
T
Pedersen
Jan M
JM
Schiøtt
Birgit
B
Tajkhorshid
Emad
E
Skrydstrup
Troels
T
Nielsen
Niels Chr
NC
D000408:Alamethicin / Q000737:chemistry / Q000378:metabolism*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010742:Phospholipid Ethers / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014867:Water / Q000378:metabolism
C052298:1,2-dihexadecyl-sn-glycero-3-phosphocholine; D000890:Anti-Infective Agents; D008051:Lipid Bilayers; D010742:Phospholipid Ethers; D014867:Water; D000408:Alamethicin; D004134:Dimyristoylphosphatidylcholine