Uncovering allostery and regulation in SORCIN through molecular dynamics simulations

Abstract

Soluble resistance-related calcium-binding protein or Sorcin is an allosteric, calcium-binding Penta-EF hand (PEF) family protein implicated in multi-drug resistant cancers. Sorcin is known to bind chemotherapeutic molecules such as Doxorubicin. This study uses in-silico molecular dynamics simulations to explore the dynamics and allosteric behavior of Sorcin in the context of Ca²⁺ uptake and Doxorubicin binding. The results show that Ca²⁺ binding induces large, but reversible conformational changes in the Sorcin structure which manifest as rigid body reorientations that preserve the local secondary structure. A reciprocal allosteric handshake centered around the EF5 hand is found to be key in Sorcin dimer formation and stabilization. Binding of Doxorubicin results in rearrangement of allosteric communities which disrupts long-range allosteric information transfer from the N-terminal domain to the middle lobe. However, this binding does not result in secondary structure destabilization. Sorcin does not appear to have a distinct Ca²⁺ activated mode of Doxorubicin binding.

Communicated by Ramaswamy H. Sarma

Keywords:

• Sorcin
• molecular dynamics
• allostery
• calcium-binding proteins

Author contributions

IA and VS performed the simulations and carried out the analysis. The study was conceived by AB and SB. The paper was composed and edited by SB, AB with assistance from VS.

Disclosure statement

The authors confirm that there are no known conflicts of interest associated with this publication.

Additional information

Funding

SB acknowledges the HPC resources provided by the National Supercomputing Mission (DST/NSM/R&D_HPC Applications/2021/03.26) and SERB (MTR/2020/000334).