Uncovering allostery and regulation in SORCIN through molecular dynamics simulations

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Soluble resistance-related calcium-binding protein (Sorcin) is a calcium-binding protein involved in multi-drug resistant cancers.
• Sorcin is known to interact with chemotherapeutic agents like Doxorubicin.

Purpose of the Study:

• To investigate the dynamics and allosteric behavior of Sorcin during calcium (Ca2+) uptake and Doxorubicin binding.
• To elucidate the structural mechanisms underlying Sorcin's function in drug resistance.

Main Methods:

• Utilized in-silico molecular dynamics simulations.
• Analyzed Ca2+ binding effects on Sorcin conformation.
• Examined Doxorubicin interaction with Sorcin structure and dynamics.

Main Results:

• Ca2+ binding induces significant, reversible conformational changes in Sorcin, characterized by rigid body reorientations that maintain secondary structure.
• A reciprocal allosteric interaction centered on the EF5 hand is crucial for Sorcin dimer formation and stability.
• Doxorubicin binding rearranges allosteric networks, impairing long-range communication but not destabilizing secondary structures.
• No distinct Ca2+-activated mode for Doxorubicin binding to Sorcin was observed.

Conclusions:

• Sorcin's conformational flexibility is modulated by Ca2+ binding, facilitating dimerization.
• Doxorubicin interaction affects Sorcin's allosteric signaling pathways without compromising its structural integrity.
• These findings provide insights into Sorcin's role in chemoresistance and potential therapeutic targeting.