245
8 Molecular Dynamics Simulations of Lipid Bilayers with Incorporated Peptides
and larger proteins starting with simple artificial peptides (see e.g. [23–25]). Later,
naturally occurred integral proteins such as channel forming peptides gramicidin A
[26, 27] and alamethicin [30], or larger transmembrane protein bacteriorhodopsin
[28, 29] were analyzed. The specially designed model peptides were also studied.
They consist typically from hydrophobic core (usually leucine (Leu) residues [31]
or in combination with alanine (Ala) [32]). This alternation of residues decreases
the core hydrophobicity and peptide better mimics the natural proteins [33]. These
peptides are flanked at both sides by hydrophilic residues stabilizing both ends in
headgroup region of the lipid bilayer. As the anchors usually lysine (Lys) [11, 34]
or tryptophan (Trp) [35] are used. In a membrane these model peptides form stable
α-helix [36, 37], even without polar anchors [38]. The evidence of peptide tilting or
changing in membrane thickness is the basis for stating the “hydrophobic matching” theory (more can be found in review published by e.g. Killian [39] or Lee [40]).
Among most used are model structures are L 24 , P 24 , WALP 19 and longer WALP 23
with two more (LA) repeating pairs [41, 42]. But also other peptide lengths were
tested—e.g. P 16 [d43] or different peptides—KWALP 23 : acetyl-G-K-A-L-W-(LA) 6 -
W-L-A-K-A-amid. The peptide–lipid interactions were studied in many lipid bilayers composed of various phosphatidylcholines (PC): dilauroyl PC (DLPC), dimyristoyl PC (DMPC). dipalmitoyl PC (DPPC), dioleoyl PC (DOPC), palmityloleoyl
PC (POPC). The MD e.g. Tieleman et al. [30] and NMR studies [42] indicated that
although helix is stable in a membrane, some parts of it were bended or even kinked.
There exists a difference in binding to a membrane the peptides flanking with Trp
and Lys residues. Maurits et al. [44] studied WALP and KALP peptides of different lengths. The WALP 16 (acetyl-G-K 2 -(LA) 5 -K 2 -A-amid) peptide in DOPC bilayer
converts membrane into inverted hexagonal H II phase, while KALP 16 remains in LC
state. In general the behavior of KALP 23 in a membrane is similar to that of WALP 21
and consisting in peptide tilt and in inducing changes in the thickness of surrounding lipid layer. This is due to firm interaction of indole group of the peptide with
carbonyl group of lipids, while the Lys amino group NH 3
+
lies at the end of long
flexible chain. Therefore Lys residue is able to snorkel into (thicker) membrane.
De Jesus and Allen [45, 46] simulated WALP peptides with different number
of Trp repeating. The longer Trp parts were used, the higher tilt has been detected
(with positive mismatch). The negative mismatch resulted in increases of the membrane deflection, decreases in lipid chain ordering and peptide gets shorter. They
also simulated long (92 amino acids) poly-Leu helical peptide with inserted Trp or
its analogue 3-methylindol (3-MIND). Trp and 3-MIND lower membrane deflection and interacts with glycerol core, carbonyl oxygens and (farther from membrane
center) with phosphate oxygen.
8.1.1 Membrane (Dis-)ordering
Lewis et al. [47] measured energetic effect of transfer the Lys-flanked peptides into
the membrane. They found the presence of helix, but also observed the decrease of
temperature and enthalpy of phase transition. This suggests that the peptides decrease ordering of membrane in a gel state. Simulations of peptides with membrane
8 Molecular Dynamics Simulations of Lipid Bilayers with Incorporated Peptides
and larger proteins starting with simple artificial peptides (see e.g. [23–25]). Later,
naturally occurred integral proteins such as channel forming peptides gramicidin A
[26, 27] and alamethicin [30], or larger transmembrane protein bacteriorhodopsin
[28, 29] were analyzed. The specially designed model peptides were also studied.
They consist typically from hydrophobic core (usually leucine (Leu) residues [31]
or in combination with alanine (Ala) [32]). This alternation of residues decreases
the core hydrophobicity and peptide better mimics the natural proteins [33]. These
peptides are flanked at both sides by hydrophilic residues stabilizing both ends in
headgroup region of the lipid bilayer. As the anchors usually lysine (Lys) [11, 34]
or tryptophan (Trp) [35] are used. In a membrane these model peptides form stable
α-helix [36, 37], even without polar anchors [38]. The evidence of peptide tilting or
changing in membrane thickness is the basis for stating the “hydrophobic matching” theory (more can be found in review published by e.g. Killian [39] or Lee [40]).
Among most used are model structures are L 24 , P 24 , WALP 19 and longer WALP 23
with two more (LA) repeating pairs [41, 42]. But also other peptide lengths were
tested—e.g. P 16 [d43] or different peptides—KWALP 23 : acetyl-G-K-A-L-W-(LA) 6 -
W-L-A-K-A-amid. The peptide–lipid interactions were studied in many lipid bilayers composed of various phosphatidylcholines (PC): dilauroyl PC (DLPC), dimyristoyl PC (DMPC). dipalmitoyl PC (DPPC), dioleoyl PC (DOPC), palmityloleoyl
PC (POPC). The MD e.g. Tieleman et al. [30] and NMR studies [42] indicated that
although helix is stable in a membrane, some parts of it were bended or even kinked.
There exists a difference in binding to a membrane the peptides flanking with Trp
and Lys residues. Maurits et al. [44] studied WALP and KALP peptides of different lengths. The WALP 16 (acetyl-G-K 2 -(LA) 5 -K 2 -A-amid) peptide in DOPC bilayer
converts membrane into inverted hexagonal H II phase, while KALP 16 remains in LC
state. In general the behavior of KALP 23 in a membrane is similar to that of WALP 21
and consisting in peptide tilt and in inducing changes in the thickness of surrounding lipid layer. This is due to firm interaction of indole group of the peptide with
carbonyl group of lipids, while the Lys amino group NH 3
+
lies at the end of long
flexible chain. Therefore Lys residue is able to snorkel into (thicker) membrane.
De Jesus and Allen [45, 46] simulated WALP peptides with different number
of Trp repeating. The longer Trp parts were used, the higher tilt has been detected
(with positive mismatch). The negative mismatch resulted in increases of the membrane deflection, decreases in lipid chain ordering and peptide gets shorter. They
also simulated long (92 amino acids) poly-Leu helical peptide with inserted Trp or
its analogue 3-methylindol (3-MIND). Trp and 3-MIND lower membrane deflection and interacts with glycerol core, carbonyl oxygens and (farther from membrane
center) with phosphate oxygen.
8.1.1 Membrane (Dis-)ordering
Lewis et al. [47] measured energetic effect of transfer the Lys-flanked peptides into
the membrane. They found the presence of helix, but also observed the decrease of
temperature and enthalpy of phase transition. This suggests that the peptides decrease ordering of membrane in a gel state. Simulations of peptides with membrane