247
8 Molecular Dynamics Simulations of Lipid Bilayers with Incorporated Peptides
Similar study has been published by Li et al. [55]. They simulated analogue of
Arg side chain—MguanH
+
. In all membranes tested they detected the ion induced
defect. In thinner membranes (DDPC, DLPC) the peptide chain even caused its
perforation. The peptide caused increase of lipid area by 0.03 nm
2
/lipid for DDPC,
while decrease of the area (by 0.03 nm
2
/lipid) has been observed for e.g. DLPC or
DSPC. This was caused by ordering or disordering of lipid chains, respectively, and
agrees with experimental data [56].
Lam et al. [57] studied the antimicrobial peptide protegrin-1 in a membrane by
atomic force microscopy (AFM) and MD methods. This 18 amino acid peptide
contains six Arg residues and created “edge instabilities” in low concentrations and
“wormhole” structure in high concentrations.
MacCallum et al. [58] simulated different amino acid interactions with DOPC
membrane. The most hydrophobic amino acids (Ile, Leu, Val, Ala) incorporate into
middle part of membrane—lowest energy has been found for Ile (− 22 kJ/mol) and
highest for Ala (− 8 kJ/mol). Cys and Met were located at region between hydrocarbon chains and beginning of choline groups (carbonyl groups)—Region II. Amino
acids with aromatic side chains Tyr, Trp, Phe had energetic minimum also in this region. But Tyr has positive energy in Region I (acyl chains). The same holds for Phe.
Trp is allowed to be localized in Region I, but with higher energy than in Region
II. Polar amino acids Asn, Gln, Ser, Thr have also energetic minimum in Region
II, but in Region I they have high positive energy (24–13 kJ/mol). The charged
amino acids Arg, Lys, Glu, Asp also prefer Region II. But the negatively charged
amino acids show steady increase of energy from water to center of the membrane,
while positively charged ones have minimum of the energy in Reg. II, which then
increase toward the center. All charged amino acids cause large water defects in a
membrane and all but (possibly) Arg lose their charge in the middle of the membrane. In similar work published by Yoo et al. [59] using free energy perturbations
method—the pK a of Arg in DPPC membrane has been estimated. The simulation
shows that pK a > 7 (center of membrane has neutral pH = 7). This means, the Arg is
probably charged in the middle of membrane.
Daily et al. [47] measured
2
H-NMR splittings of KWALP 23 peptide (acetyl-GK-A-L-W-(LA) 6 -x-W-L-A-K-A-amid) in DLPC, DMPC and DOPC membranes.
The fitting of splittings of middle six amino acids doesn’t fit to helix in the DLPC
and DMPC membranes. This suggests creation of kink of 9–13° in this region. The
same defect was detected in previous study of WALP 23 in DLPC bilayers. However
significant improvement of previous fitting of the same authors resulted in 15° kink.
In the thicker DOPC membranes the peptides didn’t exhibited this effect.
Kim and Im [60] used PMF method (potential mean force) in simulations of
WALP n (n = 16, 19, 23, 27) peptides in DMPC or POPC membrane. They also mutated Trp flanking residues with Ala, Lys and Arg. Their results can be summarized as follows: (1) tilting of a single-pass transmembrane (TM) helix is the major
response to a hydrophobic mismatch; (2) TM helix tilting up to ~10° is inherent
due to the intrinsic entropic contribution arising from helix precession around the
membrane normal even under a negative mismatch; (3) the favorable helix–lipid
interaction provides additional driving forces for TM helix tilting under a positive
8 Molecular Dynamics Simulations of Lipid Bilayers with Incorporated Peptides
Similar study has been published by Li et al. [55]. They simulated analogue of
Arg side chain—MguanH
+
. In all membranes tested they detected the ion induced
defect. In thinner membranes (DDPC, DLPC) the peptide chain even caused its
perforation. The peptide caused increase of lipid area by 0.03 nm
2
/lipid for DDPC,
while decrease of the area (by 0.03 nm
2
/lipid) has been observed for e.g. DLPC or
DSPC. This was caused by ordering or disordering of lipid chains, respectively, and
agrees with experimental data [56].
Lam et al. [57] studied the antimicrobial peptide protegrin-1 in a membrane by
atomic force microscopy (AFM) and MD methods. This 18 amino acid peptide
contains six Arg residues and created “edge instabilities” in low concentrations and
“wormhole” structure in high concentrations.
MacCallum et al. [58] simulated different amino acid interactions with DOPC
membrane. The most hydrophobic amino acids (Ile, Leu, Val, Ala) incorporate into
middle part of membrane—lowest energy has been found for Ile (− 22 kJ/mol) and
highest for Ala (− 8 kJ/mol). Cys and Met were located at region between hydrocarbon chains and beginning of choline groups (carbonyl groups)—Region II. Amino
acids with aromatic side chains Tyr, Trp, Phe had energetic minimum also in this region. But Tyr has positive energy in Region I (acyl chains). The same holds for Phe.
Trp is allowed to be localized in Region I, but with higher energy than in Region
II. Polar amino acids Asn, Gln, Ser, Thr have also energetic minimum in Region
II, but in Region I they have high positive energy (24–13 kJ/mol). The charged
amino acids Arg, Lys, Glu, Asp also prefer Region II. But the negatively charged
amino acids show steady increase of energy from water to center of the membrane,
while positively charged ones have minimum of the energy in Reg. II, which then
increase toward the center. All charged amino acids cause large water defects in a
membrane and all but (possibly) Arg lose their charge in the middle of the membrane. In similar work published by Yoo et al. [59] using free energy perturbations
method—the pK a of Arg in DPPC membrane has been estimated. The simulation
shows that pK a > 7 (center of membrane has neutral pH = 7). This means, the Arg is
probably charged in the middle of membrane.
Daily et al. [47] measured
2
H-NMR splittings of KWALP 23 peptide (acetyl-GK-A-L-W-(LA) 6 -x-W-L-A-K-A-amid) in DLPC, DMPC and DOPC membranes.
The fitting of splittings of middle six amino acids doesn’t fit to helix in the DLPC
and DMPC membranes. This suggests creation of kink of 9–13° in this region. The
same defect was detected in previous study of WALP 23 in DLPC bilayers. However
significant improvement of previous fitting of the same authors resulted in 15° kink.
In the thicker DOPC membranes the peptides didn’t exhibited this effect.
Kim and Im [60] used PMF method (potential mean force) in simulations of
WALP n (n = 16, 19, 23, 27) peptides in DMPC or POPC membrane. They also mutated Trp flanking residues with Ala, Lys and Arg. Their results can be summarized as follows: (1) tilting of a single-pass transmembrane (TM) helix is the major
response to a hydrophobic mismatch; (2) TM helix tilting up to ~10° is inherent
due to the intrinsic entropic contribution arising from helix precession around the
membrane normal even under a negative mismatch; (3) the favorable helix–lipid
interaction provides additional driving forces for TM helix tilting under a positive