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

Abstract

The proton conduction of transmembrane influenza virus B M2 (BM2) proton channel is possibly mediated by the membrane environment, but the detailed molecular mechanism is challenging to determine. In this work, how membrane lipid composition regulates the conformation and hydration of BM2 channel is elucidated in silico. The appearance of several important hydrogen-bond networks has been discovered, as the addition of negatively charged lipid palmitoyloleoyl phosphatidylglycerol (POPG) and cholesterol reduces membrane fluidity and augments membrane rigidity. A more rigid membrane environment is beneficial to expand the channel, allow more water to enter the channel, promote channel hydration, and then even affect the proton conduction facilitated by the hydrated channel. Thus, membrane environment could be identified as an important influence factor of conformation and hydration of BM2. These findings can provide a unique perspective for understanding the mechanism of membrane lipid composition regulating conformation and hydration of BM2 and have important significance to the further study of anti-influenza virus B drugs.

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

“…These revealed that Phe5 tetrad of BM2 formed a larger outward-facing phenylene ring conformation than Val27 tetrad of AM2. Hence Phe5 could not block AMT from entering the BM2 channel pore, which is consistent with experimental findings , and our previous work …”

“…Hence Phe5 could not block AMT from entering the BM2 channel pore, which is consistent with experimental findings 8,27 and our previous work. 12 Interestingly, we observed that when AMT adopted the up binding mode bound to BM2 channel, the free-energy barrier was smaller than the down binding mode (Figure S2). The smaller energy barrier suggested AMT might favor the up binding mode in the BM2 channel pore.…”

“…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 .…”

Active Binding Modes of Caffeine with Cytochrome P450 1A2 Determine Its Metabolite Profiles

“…His53, His62, His185, His208, His224, His290, His378, His388, His416, His501, and His506 were protonated at ε nitrogen atom. As we know, CYP is a kind of membrane protein, and previous research has found that the membrane environment is essential for the function of membrane proteins. , The influence of the membrane environment is reflected in the structural changes during the simulation. For CYP1A2, the existing membrane environment could help stabilize the secondary structures (A′ helix, B-C loop, F-G loop, and so on).…”

“…Generally, CYP1A2 is a structurally conserved transmembrane protein like other CYPs. As a membrane protein, the existence of a membrane environment is essential for the function of CYP1A2, according to our previous work. , The transmembrane segment of membrane proteins is hard to determined, and only the cytoplasmic structure of CYP1A2 was identified successfully by Johnson et al …”