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

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• The sarcoplasmic reticulum Ca2+-ATPase (SERCA) is crucial for muscle contraction, transporting calcium ions and protons across the sarcoplasmic reticulum membrane.
• SERCA utilizes ATP hydrolysis to pump Ca2+ ions and facilitates proton transport to maintain charge balance.
• A transient water-filled pore in SERCA has been identified, but its role in passive proton transport remains unclear.

Purpose of the Study:

• To investigate the capacity of the SERCA water-filled pore to sustain passive proton transport.
• To quantify the free energy profile and timescale of proton transport through this pathway.
• To elucidate the mechanism of passive proton flow across the sarcoplasmic reticulum.

Main Methods:

• Multiscale reactive molecular dynamics simulations.
• Free energy sampling techniques.
• Explicit accounting for dynamically coupled hydration changes within the pore.

Main Results:

• Proton transport from the central binding site to the lumen occurs on a microsecond timescale.
• A novel passive cytoplasm-to-lumen proton flow mechanism was identified.
• This pathway acts as a functional conduit for passive proton transport, distinct from active Ca2+ transport.

Conclusions:

• The SERCA water-filled pore supports passive proton transport with a microsecond timescale.
• This finding reveals a previously unknown passive proton flow mechanism in the sarcoplasmic reticulum.
• The identified pathway is proposed to be functionally significant for proton transport across the membrane.