Exploration of Ca⁺² Binding Affinity to DEAD-Box Helicase through Computational Approaches

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an occasional catastrophic fatal autosomal dominant or recessive inherited disease that affects an estimated ≈1-5000/10000 people including children, adolescents and young adults, which may cause syncope, abrupt cardiac death during exercise and emotional state. Calmodulin (CALM) functions as a messenger protein of intracellular Ca⁺² signaling in cardiomyocytes that transmits complex Ca⁺² ions to the proteins involved in cardiac contraction, and its activation is also facilitated by the binding of Ca⁺² ions. CALM structure contains 4 EF-hands, each EF-hand holds a single Ca⁺² ion (designated as, CA149, CA150, CA151 and CA152). In this study, we performed detailed in_silico analysis of normal and mutated (ASN53ILE) CALM structures to characterize their Ca⁺² binding abilities. In CALM^-ASN53ILE-Pep-IQ complex, we observed a binding shift of P68(Pep-IQ) as compared to CALM^-WT. The root mean square deviation was in the range of 0.4-1 nm for all the systems, while root mean square fluctuation values were in the range of 0.3-0.6 nm for bound versus unbound proteins. Hydrogen-bond profiling was significantly different between CALM^-WT and CALM^-ASN53ILE over the course of simulation. We observed an introduction of β1 and β2-segment between α1- α2 and α3- α4 along with the movement of C-terminal approximately to 180⁰ in the apo-CALM^-ASN53ILE. Thus, we propose that, ASN53ILE has a pathological impact in the progression of CPVT due to structural and conformational changes in CALM and its binding affinity towards P68(Pep-IQ). The current study may constitute a valuable starting point for CPVT therapeutics through the involvement of CALM^-ASN53ILE for designing novel inhibitors to cope with neuropathological disorder.