Molecular dynamics, thermodynamic, and mutational binding studies for tumor-specific LyP-1 in complex with p32
Molecular dynamics, thermodynamic, and mutational binding studies for tumor-specific LyP-1 in complex with p32
复制标题
DOI：
10.1080/07391102.2017.1313779
复制
发表时间：
2018-04
影响因子：
4.4
通讯作者：
S. Timur;Gozde Yalcin;Ö. Çevik;Cenk A Andac;R. N. Gürsoy
中科院分区：
文献类型：
--
作者：
S. Timur;Gozde Yalcin;Ö. Çevik;Cenk A Andac;R. N. Gürsoy
近年来对肿瘤归巢肽的研究表明，LyP-1（CGNKRTRGC）对肿瘤细胞具有特异性。在本工作中，我们评估了环LyP-1和它的受体，p32之间的可能的相互作用，分子动力学和对接研究，以引导新的LyP-1衍生物的设计，它可以更有效地结合到p32和执行增强的抗肿瘤作用。通过MM-PBSA热力学计算得到了p32.LyP-1复合物的总结合焓，并通过显式水分子动力学计算表明了p32.LyP-1复合物在水中的可溶解性.最后30 ns的分子动力学轨迹显示LyP-1与p32的内表面链，特别是与链B和C的强相互作用。ALA-SCAN诱变研究表明Asn 3、Lys 4、Arg 5和Arg 7氨基酸残基对LyP-1的特异性结合具有相当大的影响。在了解p32受体在癌细胞代谢中的关键作用的基础上，本研究可以通过用LyP-1衍生物作为活性靶向部分靶向p32来进一步发展抗癌治疗。这些数据也可用于开发新的药物递送系统，其中LyP-1可用于其靶向和抗癌特性。
Recent studies in tumor homing peptides have shown the specificity of LyP-1 (CGNKRTRGC) to tumor lymphatics. In this present work, we evaluated the possible interactions between cyclic LyP-1 and its receptor, p32, with molecular dynamics and docking studies in order to lead the design of novel LyP-1 derivatives, which could bind to p32 more effectively and perform enhanced antitumor effect. The total binding enthalpy energies have been obtained by MM-PBSA thermodynamic computations and the favorability of p32.LyP-1 complex in water has been shown by explicit water MD computations. The last 30 ns of molecular dynamics trajectory have shown the strong interaction of LyP-1 with the inner surface chains of p32, especially with chains B and C. ALA-SCAN mutagenesis studies have indicated the considerable influence of Asn3, Lys4, Arg5, and Arg7 amino acid residues on the specific binding of LyP-1. Within the knowledge of the critical role of p32 receptor in cancer cell metabolism, this study can lead to further developments in anticancer therapy by targeting p32 with LyP-1 derivatives as active targeting moiety. This data can also be applied for the development of new drug delivery systems in which LyP-1 can be used for its targeting and anticancer properties.