Understanding Calcium-Dependent Conformational Changes in S100A1 Protein: A Combination of Molecular Dynamics and Gene Expression Study in Skeletal Muscle

Abstract

The S100A1 protein, involved in various physiological activities through the binding of calcium ions (Ca2+), participates in several protein-protein interaction (PPI) events after Ca2+-dependent activation. The present work investigates Ca2+-dependent conformational changes in the helix-EF hand-helix using the molecular dynamics (MD) simulation approach that facilitates the understanding of Ca2+-dependent structural and dynamic distinctions between the apo and holo forms of the protein. Furthermore, the process of ion binding by inserting Ca2+ into the bulk of the apo structure was simulated by molecular dynamics. Expectations of the simulation were demonstrated using cluster analysis and a variety of structural metrics, such as interhelical angle estimation, solvent accessible surface area, hydrogen bond analysis, and contact analysis. Ca2+ triggered a rise in the interhelical angles of S100A1 on the binding site and solvent accessible surface area. Significant configurational regulations were observed in the holo protein. The findings would contribute to understanding the molecular basis of the association of Ca2+ with the S100A1 protein, which may be an appropriate study to understand the Ca2+-mediated conformational changes in the protein target. In addition, we investigated the expression profile of S100A1 in myoblast differentiation and muscle regeneration. These data showed that S100A1 is expressed in skeletal muscles. However, the expression decreases with time during the process of myoblast differentiation.

Molecular Basis of S100A1 Activation and Target Regulation Within Physiological Cytosolic Ca2+ Levels

“…Similar to most members of the S100 class of Ca 2+ binding proteins, S100A1 activation proceeds through binding of two Ca 2+ , one each at the low-affinity pEF and high affinity cEF hands. In its fully-saturated, Ca 2+ -bound (holo) state, S100A1 presents a hydrophobic patch between helices three and four (H3 and H4) that enable binding to regulatory domains of protein targets (Wright et al, 2005;Nowakowski et al, 2011), which may be accompanied by significant increases in solvent accessible surface area relative to the apo state (Chaturvedi et al, 2020). In the absence of Ca 2+ (apo state), the hydrophobic patch is concealed by closing the H3/H4 hinge region (Figure 1) (Nowakowski et al, 2011).…”

Plasma S100A1 protein: An effective prognostic biomarker for 3-month clinical outcome in acute ischemic stroke patients

“…This protein is a calcium-binding protein primarily found in vertebrates due to its ability to bind calcium ions. 25,26 The S100 protein family currently consists of 25 members with a high degree of sequence and structural similarity. In diverse tissues, they participate in intracellular and extracellular regulatory processes.…”