Long-Timescale Molecular Dynamics Reveal a Coordination-Biased Conformational Selection Mechanism for Sorcin...

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Dynamics

Background:

• Sorcin is a dimeric Ca2+-binding protein regulating intracellular Ca2+ homeostasis and implicated in cancer multidrug resistance.
• Crystal structures show Sorcin's inactive (apo) and active (Ca2+-bound) states, but the transition pathways and conformational ensembles are unclear.

Purpose of the Study:

• To elucidate the Ca2+-coupled conformational landscape of dimeric human Sorcin at atomic resolution using long-timescale molecular dynamics simulations.
• To understand the dynamic mechanisms underlying Sorcin's activation and inactivation in response to Ca2+ binding and dissociation.

Main Methods:

• Utilized ~90 μs of all-atom molecular dynamics simulations on Anton 3 for human Sorcin.
• Simulations were initiated from both Ca2+-bound and apo crystal structures to observe transitions and conformational sampling.

Main Results:

• Directly observed the microsecond-timescale transition from active to inactive states upon Ca2+ removal.
• Revealed ultrafast Ca2+ dissociation/rebinding, indicating weak intrinsic Ca2+ affinity and dynamic ion exchange.
• Observed spontaneous sampling of active-like conformations in the apo state, supporting conformational selection.
• Detected persistent structural asymmetry between Sorcin protomers, highlighting dynamic heterogeneity.

Conclusions:

• Supported a coordination-biased conformational selection model for Sorcin activation.
• Proposed that weak, rapidly exchanging Ca2+ binding stabilizes the active state rather than inducing it.
• Provided a dynamic framework for Sorcin's function as a fast Ca2+ sensor and insights into EF-hand protein activation.