Ray Anushka, Macwan Isaac, Singh Shrishti, Silwal Sushila, Patra Prabir
Nashua High School South, Nashua, NH 03062, USA.
Department of Biomedical Engineering, University of Bridgeport, Bridgeport, CT 06604, USA.
Nanomaterials (Basel). 2018 Jan 23;8(2):57. doi: 10.3390/nano8020057.
During a heart failure, an increased content and activity of nucleoside diphosphate kinase (NDPK) in the sarcolemmal membrane is responsible for suppressing the formation of the second messenger cyclic adenosine monophosphate (cAMP)-a key component required for calcium ion homeostasis for the proper systolic and diastolic functions. Typically, this increased NDPK content lets the surplus NDPK react with a mutated G protein in the beta-adrenergic signal transduction pathway, thereby inhibiting cAMP synthesis. Thus, it is thus that inhibition of NDPK may cause a substantial increase in adenylate cyclase activity, which in turn may be a potential therapy for end-stage heart failure patients. However, there is little information available about the molecular events at the interface of NDPK and any prospective molecule that may potentially influence its reactive site (His118). Here we report a novel computational approach for understanding the interactions between graphene oxide (GO) and NDPK. Using molecular dynamics, it is found that GO interacts favorably with the His118 residue of NDPK to potentially prevent its binding with adenosine triphosphate (ATP), which otherwise would trigger the phosphorylation of the mutated G protein. Therefore, this will result in an increase in cAMP levels during heart failure.
在心力衰竭期间，肌膜中核苷二磷酸激酶（NDPK）含量和活性的增加会抑制第二信使环磷酸腺苷（cAMP）的形成，而cAMP是钙离子稳态以及正常收缩和舒张功能所需的关键成分。通常，NDPK含量的增加会使多余的NDPK与β-肾上腺素能信号转导途径中的突变G蛋白发生反应，从而抑制cAMP的合成。因此，抑制NDPK可能会导致腺苷酸环化酶活性大幅增加，这反过来可能是终末期心力衰竭患者的一种潜在治疗方法。然而，关于NDPK与任何可能潜在影响其反应位点（His118）的潜在分子之间界面处的分子事件，目前几乎没有相关信息。在此，我们报告一种用于理解氧化石墨烯（GO）与NDPK之间相互作用的新型计算方法。通过分子动力学发现，GO与NDPK的His118残基发生有利相互作用，从而可能阻止其与三磷酸腺苷（ATP）结合，否则ATP会触发突变G蛋白的磷酸化。因此，这将导致心力衰竭期间cAMP水平升高。
