Biomedical Engineering Reference
In-Depth Information
5.7.1 MD Techniques
We considered five different relative locations and orientations randomly generated in
each drug-lipid complex as initial structures for MD simulations. For each location-
and orientation-specific complex, a 6 ns (chemotherapy drugs) or 10 ns (gA or Alm)
explicit water MD simulation at 300 K in a solution at pH 7 was performed. We
applied the software package Amber 11 [ 84 ], specifically the Amber force field ff03
was used. The explicit water TIP3P model was used to simulate solvent effects. The
force field parameters for drugs and lipids (PC and PS) were generated using an
Amber module antechamber [ 28 , 77 ]. Twenty complexes were energy-minimized
using the steepest descent method for the first ten cycles, and then followed by
a conjugate gradient for another one thousand cycles. We then applied Langevin
dynamics during the process of heating up the system for 200 ps with the energy-
minimized complex, in which drug and lipid molecules were being restrained using
a harmonic potential with a force constant k
100 N/m. Afterward, we introduced
pressure regulation to equilibrate water molecules around the complex, and to reach
an equilibrium density for another 200 ps in addition to temperature regulation. The
MD production run then was continued for 6 ns. Note that the phospholipid was gently
restrained with a harmonic potential with a force constant k
=
=
10 N/m, applied only
to the phosphate during the production runs.
5.7.2 MD Results and Discussion
The Drug/Peptide Lipid Physical Interactions as a Possible Cause
of Their Induced Pore Formation
MD results presented in Figs. 5.26 and 5.27 suggest that the drug/ peptide lipid com-
plex fluctuates within a separation over a period of time. These results suggest that
both drugs and peptides likely bind with PC and PS given appropriate initial condi-
tions [ 15 ]. In the in-depth analysis, we found evidence suggesting that the hydropho-
bic effect is unlikely to contribute into the distance dependent drug/peptide lipid
binding. The analysis of energy contributions from two non-bonded interactions,
E vdW and E ES versus d drug lipid revealed crucial insights into the cause of the
observed stability of the drug/peptide lipid complexes. Both E vdW and E ES appear to
be the main contributors to the energetic drug/peptide lipid binding and vdW inter-
actions contribute slightly more than ES interactions as the drug and lipid approach
closer. Binding stability generally is found to decrease quickly with increasing
d drug lipid . Both vdW and ES interactions contribute comparably with both ener-
gies decreasing with increasing d drug lipid . Large standard deviations (Figs. 5.26 and
5.27 ) are suggestive of the conformational space of the drug/peptide lipid complexes
not being completely explored in MD simulations. Nonetheless, this incomplete-
ness does not preclude the proposed interpretation. Importantly, the drug/peptide
 
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