What are the effects of the serine triad on proton conduction of an influenza B M2 channel? An investigation by molecular dynamics simulations

Abstract

A novel viewpoint about the effects of serine triad on proton conduction in a BM2 channel was proposed.

In Silico Study of Membrane Lipid Composition Regulating Conformation and Hydration of Influenza Virus B M2 Channel

“…The probability density distributions of the conformation divided the curves into two populations with the relative weight shifting (Figure A): one is centered at 2.4–2.7 Å, representing the closed state, and the other has a wider distribution centered at 5.2–6.2 Å, adopting the open state. Interestingly, whether in negatively charged membrane or neutral membrane, the BM2 channel remained the closed state in His19 4 0 and adopted the open state in His19 4 4+ , consistent with our previous work. , Increase in RMSD is similar: 12% (from 2.4 to 2.7 Å) in His19 4 0 and 20% (from 5.2 to 6.2 Å) in His19 4 4+ . Compared to the neutral membrane, RMSD increased more in negatively charged membrane (Figure A), especially in the full-cationic state His19 4 4+ .…”

“…Experimental and theoretical investigations elucidated that hydration in the pore plays an important role in the proton conduction process. ,,,,,,− Proton conduction at a low pH is facilitated by an expanded channel width and increased hydration. ,, Our previous work demonstrated that the widely open channel of BM2 (His19 4 4+ ) could allow more water molecules to enter the channel and form the complete water wire, and then strengthen channel hydration. As mentioned above, a negatively charged membrane facilitates expanding channel.…”

“…Additionally, a high cholesterol level would also play a prominent role in promoting channel widening. The expanding channel is beneficial for hydration and proton conduction. , In the following, we would clarify how the presence of cholesterol modulates channel hydration.…”

“…The high-resolution NMR structure of BM2 (PDB: 2KIX, model 1) was obtained from the Protein Data Bank (Figure A). Based on our previous work, , the protonation states of His19, His19 4 0 (four His19 residues were neutral, τ tautomers of His19 were used, ,, representing the closed state of the BM2 channel), and His19 4 4+ (four His19 residues were all cationic, representing the open state of the BM2 channel) were chosen. Additionally, according to experimental work, , there is an equilibrium between τ tautomer and π tautomer, which gives a tautomer ratio of 3:1.…”

In Silico Analysis Revealed a Unique Binding but Ineffective Mode of Amantadine to Influenza Virus B M2 Channel

“…AM2 and BM2 are responsible for acid-activating the channel and transferring protons. ,− Therefore, M2 channel is an ideal target for anti-influenza drug design. In our previous work, we have shed light on the unique acid activation-promotion mechanism of the BM2 channel and determined the key factors of affecting acid-activation and transferring protons. − Amantadine (1-adamantanamine hydrochloride, referred to as AMT in this work) is best known to inhibit AM2 channel favoring the down binding mode (Figure ) by binding and blocking the channel pore and impeding proton transport through the pore. − However, there is no effective inhibitor or drug against BM2 channel. AMT lacks inhibitory activity against BM2 channel, which has a highly conserved functional motif common to the AM2 channel .…”