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

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

2020 ◽  
Vol MA2020-02 (33) ◽  
pp. 2109-2109
Author(s):  
Tomohiro Matsuda ◽  
Koichi Kobayashi ◽  
Takuya Mabuchi ◽  
Gen Inoue ◽  
Takashi Tokumasu
Keyword(s):  
Proton Transport ◽  
Thickness Distribution ◽  
Catalyst Layer ◽  
Multiscale Simulation

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 The Origin of Coupled Chloride and Proton Transport in a Cl−/H+ Antiporter

2016 ◽  
Author(s):  
Sangyun Lee ◽  
Heather B. Mayes ◽  
Jessica M. J. Swanson ◽  
Gregory A. Voth
Keyword(s):  
Chemical Reaction ◽  
Proton Transport ◽  
Critical Role ◽  
Multiscale Simulation ◽  
Transport Processes ◽  
Experimental Result ◽  
Free Energy Barrier ◽  
Concentration Gradients ◽  
Extracellular Solution

AbstractThe ClC family of transmembrane proteins functions throughout nature to control the transport of Cl− ions across biological membranes. ClC-ec1 from Escherichia coli is an antiporter, coupling the transport of Cl− and H+ ions in opposite directions and driven by the concentration gradients of the ions. Despite keen interest in this protein, the molecular mechanism of the Cl−/H+ coupling has not been fully elucidated. Here, we have used multiscale simulation to help identify the essential mechanism of the Cl−/H+ coupling. We find that the highest barrier for proton transport (PT) from the intra- to extracellular solution is attributable to a chemical reaction—the deprotonation of glutamic acid 148 (E148). This barrier is significantly reduced by the binding of Cl− in the “central” site (Cl−cen), which displaces E148 and thereby facilitates its deprotonation. Conversely, in the absence of Cl−cen E148 favors the “down” conformation, which results in a much higher cumulative rotation and deprotonation barrier that effectively blocks PT to the extracellular solution. Thus, the rotation of E148 plays a critical role in defining the Cl−/H+ coupling. As a control, we have also simulated PT in the ClC-ec1 E148A mutant to further understand the role of this residue. Replacement with a non-protonatable residue greatly increases the free energy barrier for PT from E203 to the extracellular solution, explaining the experimental result that PT in E148A is blocked whether or not Cl−cen is present. The results presented here suggest both how a chemical reaction can control the rate of PT and also how it can provide a mechanism for a coupling of the two ion transport processes.

Nano/Microscale Simulation of Proton Transport in Catalyst Layer

2019 ◽  
Vol 92 (8) ◽  
pp. 515-522
Author(s):  
Koichi Kobayashi ◽  
Takuya Mabuchi ◽  
Gen Inoue ◽  
Takashi Tokumasu
Keyword(s):  
Proton Transport ◽  
Catalyst Layer

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.

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