Mutations in the cardiac ryanodine receptor type 2 (RyR2) have been linked to a variety of cardiac arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). RyR2 is regulated by calmodulin (CaM), and mutations that disrupt their interaction can cause aberrant calcium release, leading to an arrhythmia. It was recently shown that increasing the RyR2–CaM binding affinity could rescue a defective CPVT-related RyR2 channel to near wild-type behavior. However, the interactions that determine the binding affinity at the RyR2–CaM binding interface are not well understood. In this study, we identify the key domains and interactions, including several new interactions, involved in the binding of CaM to RyR2. Also, our comparison between the wild-type and V3599K mutant suggests how the RyR2–CaM binding affinity can be increased via a change in the central and N-terminal lobe binding contacts for CaM. This computational approach provides new insights into the effect of a mutation at the RyR2–CaM binding interface, and it may find utility in drug design for the future treatment of cardiac arrhythmias.

中文翻译：

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Ryanodine 受体 2 型与钙调素之间结合相互作用的计算分析

心脏兰尼碱受体 2 型 (RyR2) 的突变与多种心律失常有关，例如儿茶酚胺能多形性室性心动过速 (CPVT)。RyR2 受钙调蛋白 (CaM) 调节，破坏它们相互作用的突变会导致钙释放异常，从而导致心律失常。最近表明，增加 RyR2-CaM 结合亲和力可以将有缺陷的 CPVT 相关 RyR2 通道拯救为接近野生型的行为。然而，决定 RyR2-CaM 结合界面结合亲和力的相互作用尚不清楚。在这项研究中，我们确定了涉及 CaM 与 RyR2 结合的关键域和相互作用，包括几个新的相互作用。还，我们在野生型和 V3599K 突变体之间的比较表明，如何通过改变 CaM 的中央和 N 端叶结合接触来增加 RyR2-CaM 结合亲和力。这种计算方法为 RyR2-CaM 结合界面突变的影响提供了新的见解，它可能会在药物设计中找到用于未来治疗心律失常的实用性。