scholarly journals Multiscale Simulation of an Influenza A M2 Channel Mutant Reveals Key Features of Its Markedly Different Proton Transport Behavior

2022 ◽  
Author(s):  
Laura C. Watkins ◽  
William F. DeGrado ◽  
Gregory A. Voth
Keyword(s):  
Proton Transport ◽  
Influenza A ◽  
Multiscale Simulation ◽  
Transport Behavior ◽  
Key Features

scholarly journals Multiscale Simulation of an Influenza A M2 Channel Mutant Reveals Key Features of Its Markedly Different Proton Transport Behavior

2021 ◽  
Author(s):  
Laura C. Watkins ◽  
William F. DeGrado ◽  
Gregory A. Voth
Keyword(s):  
Free Energy ◽  
Proton Transport ◽  
Influenza A ◽  
Water Structure ◽  
Multiscale Simulation ◽  
Reactive Molecular Dynamics ◽  
Activated State ◽  
Ph Range ◽  
And Shifts

ABSTRACTThe influenza A M2 channel, a prototype for the viroporin class of viral channels, is an acid-activated viroporin that conducts protons across the viral membrane, a critical step in the viral life cycle. As the protons enter from the viral exterior, four central His37 residues control the channel activation by binding subsequent protons, which opens the Trp41 gate and allows proton flux to the viral interior. Asp44 is essential for maintaining the Trp41 gate in a closed state at high pH, which results in asymmetric conduction. The prevalent D44N mutant disrupts this gate and opens the C-terminal end of the channel, resulting in overall increased conduction in the physiologically relevant pH range and a loss of this asymmetric conduction. Here, we use extensive Multiscale Reactive Molecular Dynamics (MS-RMD) and Quantum Mechanics/Molecular mechanics (QM/MM) simulations with an explicit, reactive excess proton to calculate the free energy of proton transport in the M2 mutant and to study the dynamic molecular-level behavior of D44N M2. We find that this mutation significantly lowers the barrier of His37 deprotonation in the activated state and shifts the barrier for entry up to the Val27 tetrad. These free energy changes are reflected in structural shifts. Additionally, we show that the increased hydration around the His37 tetrad diminishes the effect of the His37 charge on the channel’s water structure, facilitating proton transport and enabling activation from the viral interior. Altogether, this work provides key insight into the fundamental characteristics of PT in WT M2 and how the D44N mutation alters this PT mechanism, and it expands our understanding of the role of emergent mutations in viroporins.

scholarly journals Proton Transport Behavior through the Influenza A M2 Channel: Insights from Molecular Simulation

2007 ◽  
Vol 93 (10) ◽  
pp. 3470-3479 ◽  
Author(s):  
Hanning Chen ◽  
Yujie Wu ◽  
Gregory A. Voth
Keyword(s):  
Molecular Simulation ◽  
Proton Transport ◽  
Influenza A ◽  
Transport Behavior

scholarly journals Multiscale Simulation Reveals Passive Proton Transport Through SERCA on the Microsecond Timescale

2020 ◽  
Author(s):  
Chenghan Li ◽  
Zhi Yue ◽  
L. Michel Espinoza-Fonseca ◽  
Gregory A. Voth
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Sarcoplasmic Reticulum ◽  
Binding Site ◽  
Proton Transport ◽  
Computational Study ◽  
Multiscale Simulation ◽  
Proton Pumping ◽  
Reactive Molecular Dynamics ◽  
Free Energy Sampling

ABSTRACTThe sarcoplasmic reticulum Ca2+-ATPase (SERCA) transports two Ca2+ ions from the cytoplasm to the reticulum lumen at the expense of ATP hydrolysis. In addition to transporting Ca2+, SERCA facilitates bidirectional proton transport across the sarcoplasmic reticulum to maintain the charge balance of the transport sites and to balance the charge deficit generated by the exchange of Ca2+. Previous studies have shown the existence of a transient water-filled pore in SERCA that connects the Ca2+-binding sites with the lumen, but the capacity of this pathway to sustain passive proton transport has remained unknown. In this study, we used the multiscale reactive molecular dynamics (MS-RMD) method and free energy sampling to quantify the free energy profile and timescale of the proton transport across this pathway while also explicitly accounting for the dynamically coupled hydration changes of the pore. We find that proton transport from the central binding site to the lumen has a microsecond timescale, revealing a novel passive cytoplasm-to-lumen proton flow beside the well-known inverse proton countertransport occurring in active Ca2+ transport. We propose that this proton transport mechanism is operational and serves as a functional conduit for passive proton transport across the sarcoplasmic reticulum.SIGNIFICANCEMultiscale reactive molecular dynamics combined with free energy sampling was applied to study proton transport through a transient water pore connecting the Ca2+-binding site to the lumen in SERCA. This is the first computational study of this large biomolecular system that treats the hydrated excess proton and its transport through water structures and amino acids explicitly. When also correctly accounting for the hydration fluctuations of the pore, it is found that a transiently hydrated channel can transport protons on a microsecond timescale. These results quantitatively support the hypothesis of the proton intake into the sarcoplasm via SERCA, in addition to the well-known proton pumping by SERCA to the cytoplasm along with Ca2+ transport.

scholarly journals Acid-Activation, Proton Transport Rate Saturation, and pH-Dependence of Amantadine Block for Influenza a M2 Protein Truncate (22-62)

2010 ◽  
Vol 98 (3) ◽  
pp. 503a ◽  
Author(s):  
Emily Peterson ◽  
Myunggi Yi ◽  
Huan-Xiang Zhou ◽  
Mukesh Sharma ◽  
Timothy A. Cross ◽  
...  
Keyword(s):  
Proton Transport ◽  
Influenza A ◽  
Ph Dependence ◽  
Transport Rate ◽  
Acid Activation ◽  
M2 Protein

Multiscale Simulation of Proton Transport in the Catalyst Layer with Consideration of Ionomer Thickness Distribution

2020 ◽  
Vol 98 (9) ◽  
pp. 187-196
Author(s):  
Tomohiro Matsuda ◽  
Koichi Kobayashi ◽  
Takuya Mabuchi ◽  
Gen Inoue ◽  
Takashi Tokumasu
Keyword(s):  
Proton Transport ◽  
Thickness Distribution ◽  
Catalyst Layer ◽  
Multiscale Simulation

scholarly journals Determining the Functional Core for Proton Transport, Ion Selectivity and Amantadine Sensitivity of the A/M2 Protein from Influenza A Virus

2009 ◽  
Vol 96 (3) ◽  
pp. 668a
Author(s):  
Chunlong Ma ◽  
Alexei Polishchuk ◽  
Yuki Ohigashi ◽  
William F. DeGrado ◽  
Robert A. Lamb ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Proton Transport ◽  
Influenza A ◽  
Ion Selectivity ◽  
M2 Protein

Two different types of channels exhibiting distinct proton transport behavior in an open-framework aluminophosphate

2018 ◽  
Vol 258 ◽  
pp. 695-701 ◽  
Author(s):  
Chen Xue ◽  
Yang Zou ◽  
Shao-Xian Liu ◽  
Xiao-Ming Ren ◽  
Zheng-Fang Tian
Keyword(s):  
Proton Transport ◽  
Open Framework ◽  
Transport Behavior ◽  
Different Types

scholarly journals Acid activation mechanism of the influenza A M2 proton channel

2016 ◽  
Vol 113 (45) ◽  
pp. E6955-E6964 ◽  
Author(s):  
Ruibin Liang ◽  
Jessica M. J. Swanson ◽  
Jesper J. Madsen ◽  
Mei Hong ◽  
William F. DeGrado ◽  
...  
Keyword(s):  
Free Energy ◽  
Proton Transport ◽  
Influenza A ◽  
Conduction Mechanism ◽  
Transmembrane Domain ◽  
Proton Conduction ◽  
Proton Flux ◽  
Activation Mechanism ◽  
Proton Channel ◽  
Acid Activation

The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2. All proton transfer steps involved in proton diffusion through the channel, including the protonation/deprotonation of His37, are explicitly considered using classical, quantum, and reactive molecular dynamics methods. The asymmetry of the proton transport free energy profile under high-pH conditions qualitatively explains the rectification behavior of AM2 (i.e., why the inward proton flux is allowed when the pH is low in viral exterior and high in viral interior, but outward proton flux is prohibited when the pH gradient is reversed). Also, in agreement with electrophysiological results, our simulations indicate that the C-terminal amphipathic helix does not significantly change the proton conduction mechanism in the AM2 transmembrane domain; the four transmembrane helices flanking the channel lumen alone seem to determine the proton conduction mechanism.

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