Biomedical Engineering Reference
In-Depth Information
curvature. Higher lipid charges strongly destabilize the probability of observing any
Alm channel current level, especially higher order current levels [ 18 ]. The higher
concentration
required in thicker bilayers or bilayers containing lipids with
negative curvature or charges are likely to change the free energy profile in bilay-
ers [ 92 ] which compensates for the changed values of the theoretically calculated
[
M Alm ]
G 1 3
of any Alm channel within a lipid bilayer system are not drastically different, which
is consistent with the calculated values of
G 1 2 and
G I , II . The experimentally observed changes in free energies
G I , II for any specific order of lipid
screening where the values of
G I , II do not considerably change due to the change
of the number of monomers in Alm channels. In particular,
G I , II values stay within
the same order of magnitude but slightly increase with the increase of the number of
Alm monomers participating in Alm channel formation mainly due to the increased
channel-bilayer interaction sites. However,
G I , II changes exponentially between
different lipid orders which can be compared with the compensation of free energy
changes [ 92 ] due to the requirement of higher geometric orders of
M gA ]
in the case of gA channels) when the bilayer thickness increases or neutral lipids are
replaced by more negative curvature bearing lipids in the bilayers.
[
M Alm ]
(or
[
5.7 Evidence of Physical Interactions Between Lipids
and Channel-Forming Peptides or Other Drugs: A Case
Study Using Molecular Dynamics Simulations
We designed an in silico molecular dynamics (MD) simulation [ 15 ] in order to model
the drug-lipid interactions and to gain deeper insights into the problem. This simu-
lation illustrates how an empirical calculation of the force field finds partial charges
on each atom in the drugs or peptides interacting with lipids on lipid membranes,
irrespective of their net molecular charges [ 24 , 43 , 44 , 53 ].
In charge-bearing peptide-induced ion channels, e.g., gA and Alm, or charge-
neutral chemotherapy drug-induced ion pores [ 14 ], both ion channel/pore form-
ing agents and lipids approach each other through hydrophobic coupling (e.g., see
Figs. 5.2 , 5.6 , 5.7 , 5.8 , 4.5 , etc.). So naturally, charges on charge-bearing lipids e.g.,
phophatidylserine (PS), phosphatidylglycerol (PG), etc. and charge-bearing peptides,
e.g., gA, Alm, etc. experience electrical fields created by each other. But what hap-
pens if both lipids and channel-forming drugs have no net molecular charges? This
question naturally appears as most of the lipids in cell membranes are zwitterionic
phosphatidylcholines (PCs) with no net electric charges. Also, the finding of channel
formation by charge neutral chemotherapy drugs [ 14 ] raises the question if there
is any possibility to observe interactions between the channel-forming drugs and
bilayer constituents, especially lipids, due to the electrical properties of drugs and
lipids in a manner equivalent to the claimed peptide lipid screened Coulomb inter-
actions in gA channels lipid bilayer binding ([ 11 ] in Chap. 4 ) . To clearly understand
this general issue we have performed MD simulations.
 
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