<p>We studied by molecular dynamic (MD)
simulations systems including the inward<sub>closed</sub> state of influenza A
M2 protein in complex with aminoadamantane drugs in membrane bilayers. We
varied the M2 construct and performed MD simulations in M2TM or M2TM with
amphipathic helices (M2AH). We also varied the lipid bilayer by changing either
the lipid, DMPC or POPC, POPE or POPC/cholesterol (chol), or the lipids buffer
size, 10x10 Å<sup>2 </sup>or 20x20 Å<sup>2</sup>. We aimed to suggest optimal
system conditions for the computational description of this ion channel and
related systems. Measures performed include quantities that are available experimentally
and include: (a) the position of ligand, waters and chlorine anion inside the M2
pore, (b) the passage of waters from the outward Val27 gate of M2 S31N in
complex with an aminoadamantane-aryl head blocker, (c) M2 orientation, (d) the
AHs conformation and structure which is affected from interactions with lipids
and chol and is important for membrane curvature and virus budding. In several
cases we tested OPLS2005, which is routinely applied to describe drug-protein
binding, and CHARMM36 which describes reliably protein conformation. We found
that for the description of the ligands position inside the M2 pore, a 10x10 Å<sup>2</sup>
lipids buffer in DMPC is needed when M2TM is used but 20x20 Å<sup>2</sup>
lipids buffer of the softer POPC; when M2AH is used all 10x10 Å<sup>2</sup> lipid
buffers with any of the tested lipids can be used. For the passage of waters at
least M2AH with a 10x10 Å<sup>2</sup> lipid buffer is needed. The folding
conformation of AHs which is defined from hydrogen bonding interactions with
the bilayer and the complex with chol is described well with a 10x10 Å<sup>2</sup>
lipids buffer and CHARMM36. </p>
Multifunctional Inhibitors of SARS CoV2 by MM/PBSA, Essential dynamics, and Molecular dynamic investigations.
