登革病毒M蛋白是具有两个螺旋跨膜(TM)的75个氨基酸的多肽。TM域寡聚化形成离子通道,促进病毒从宿主细胞释放。M蛋白在病毒进入和生命周期中起着至关重要的作用,使其成为有效的药物靶标。在隐含膜环境中使用从头算建模和分子动力学(MD)模拟研究了单体蛋白的寡聚化。获得的代表性结构显示五聚体为最稳定的寡聚态,类似于离子通道。谷氨酸,苏氨酸,丝氨酸,色氨酸,丙氨酸,异亮氨酸形成五聚体通道的孔衬残基,将整体负电荷赋予通道,长度约为51.9µ。M蛋白的残基相互作用分析(RIN)显示Ala94,Leu95,Ser112,Glu124和Phe155是代表结构域之间物理化学相互作用的中心中心残基。用来自离子通道库的165种不同离子通道抑制剂进行虚拟筛选,显示单价离子通道阻断剂,即lumacaftor,格列吡嗪,格列喹酮,格列索西定,阿折地平是对接得分高的抑制剂。了解M蛋白的三维结构将有助于设计登革热感染的治疗方法和疫苗。
The Dengue virus M protein is a 75 amino acid polypeptide with two helical transmembranes (TM). The TM domain oligomerizes to form an ion channel, facilitating viral release from the host cells. The M protein has a critical role in the virus entry and life cycle, making it a potent drug target. The oligomerization of the monomeric protein was studied using ab initio modeling and molecular dynamics (MD) simulation in an implicit membrane environment. The representative structures obtained showed pentamer as the most stable oligomeric state, resembling an ion channel. Glutamic acid, threonine, serine, tryptophan, alanine, isoleucine form the pore-lining residues of the pentameric channel, conferring an overall negative charge to the channel with approximate length of 51.9 Å. Residue interaction analysis (RIN) for M protein shows that Ala94, Leu95, Ser112, Glu124, and Phe155 are the central hub residues representing the physicochemical interactions between domains. The virtual screening with 165 different ion channel inhibitors from the ion channel library shows monovalent ion channel blockers, namely lumacaftor, glipizide, gliquidone, glisoxepide, and azelnidipine to be the inhibitors with high docking scores. Understanding the three-dimensional structure of M protein will help design therapeutics and vaccines for Dengue infection.