Molecular dynamics provides new insights into the mechanism of calcium signal transduction and interdomain interactions in cardiac troponin

Abstract

Understanding the regulation of cardiac muscle contraction at a molecular level is crucial for the development of therapeutics for heart conditions. Despite the availability of atomic structures of the protein components of cardiac muscle thin filaments, detailed insights into their dynamics and response to calcium are yet to be fully depicted. In this study, we used molecular dynamic simulations of the core domains of the cardiac muscle protein troponin to characterize the equilibrium dynamics of cardiac troponin's calcium-bound and calcium-free forms, with a focus on elements of cardiac muscle contraction activation and deactivation; that is, calcium binding to the calcium sensor troponin C domain (TnC) and the release of the switch region of the troponin inhibitory domain I (TnI) from TnC. The process of calcium binding to the TnC binding site is described as a three-step process commencing with calcium capture by the binding site residues, followed by cooperative residue interplay bringing the calcium ion to the binding site, and finally, calcium-water exchange. Furthermore, we uncovered a set of TnC-TnI inter-domain interactions, critical for TnC N-lobe hydrophobic pocket dynamics. Absence of these interactions allows the closure of the TnC N-lobe hydrophobic pocket while the TnI switch region remains expelled, whereas if the interactions are maintained the hydrophobic pocket remains open. Modification of these interactions may fine-tune the ability of the TnC N-lobe hydrophobic pocket to close or remain open, modulate cardiac contractility, and present potential therapy-relevant targets.

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

“…Given the importance of ACE2 in COVID-19,(42) this further implicates TNNI3 as an important target of severe disease pathophysiology (see Supplementary Table 5 for TNNI3 associated proteins). Levosimendan has been shown to exert action on the myocardial troponin complex,(20) (21,22)which involves complex interactions between troponin I and troponin C (43,44). Levosimendan is a calcium sensitiser, which canonically also exerts action on troponin C that is implicated in several diseases, including hypertrophic cardiomyopathy (45).…”

Therapeutic peptides for coronary artery diseases: in silico methods and current perspectives

“…3 ). MD simulations revealed the complex interdomain interactions of cardiac tropin and revealed the calcium signaling mechanism (Genchev et al 2021 ). Accordingly, Ca 2+ binding, which constitutes the first signal of cardiac contraction, is characterized by three steps: (i) the capture of calcium, (ii) interactions of residues that transport Ca 2+ ions to the binding site, and (iii) calcium-water exchange.…”

Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship

“…The hydrophobic patch serves as an attractive target for increasing Ca 2+ sensitivity via small molecules. Additionally, the hydrophobic patch and entire troponin complex have been the focus of numerous in silico studies to capture the proteins dynamics of hydrophobic patch opening 30, 31, 32, 33, 34, 35, 36, 37 , and cTnI sp binding 38, 39, 40, 41, 42 .…”