Microsecond Molecular Simulations Reveal a Transient Proton Pathway in the Calcium Pump

Area of Science:

• Biochemistry
• Structural Biology
• Membrane Transport

Background:

• The sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) is crucial for muscle contraction, transporting Ca(2+) and H(+) ions.
• SERCA utilizes separate pathways for ion transport to maintain structural integrity.
• The existence of simultaneous ion pathways during fast structural transitions remains unclear.

Purpose of the Study:

• To investigate the presence and function of simultaneous proton and metal ion pathways during fast (microsecond) structural transitions in SERCA.
• To elucidate the mechanism of proton transport during rapid SERCA conformational changes.

Main Methods:

• Analysis of microsecond-long molecular dynamics trajectories of a protonated SERCA intermediate (E1·H(+)771).
• Identification and characterization of a transient hydrophobic pore using structural analysis.
• Protein pKa calculations to assess the suitability of the pore for proton transport.

Main Results:

• A transient hydrophobic pore was identified in the luminal side of transmembrane helices 6, 8, and 9.
• This pore connects the transport site to the lumen via water molecules, facilitating proton transport.
• The pore is suitable for proton transport, as indicated by structural analysis and pKa calculations.

Conclusions:

• A transient proton pathway exists in SERCA, active during rapid structural transitions.
• This pathway neutralizes transport sites, preserving SERCA stability and optimizing Ca(2+) transport.
• The findings offer insights into ion-exchange mechanisms in P-type ATPases via transient hydrophobic pores.