MOLECULAR DYNAMICS SIMULATIONS OF BUFORIN II TRANSLOCATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 抗菌肽是传统抗生素的潜在替代品，特别是对已产生抗药性的细菌。一种耐人寻味的多肽是蟾酥素II(BF2)，它被认为通过穿过细胞膜并结合细胞内的核酸来杀死细菌。我们实验室正在进行的研究是利用各种实验技术和分子动力学(MD)模拟在分子水平上研究BF2膜的转运机制。以前，我们主要关注单个BF2肽与明确表示的脂膜相互作用的模拟，这些模拟为BF2脂膜相互作用提供了有用的见解。然而，单肽模拟不允许我们考虑多肽之间在易位方面的潜在协同作用，例如假想的环状孔的形成。因此，目前正在考虑模拟多个BF2多肽与显式脂膜的相互作用，类似于最近发表的Mainin和Tat多肽的模拟。我们正在申请一项发展拨款，以探索在这些需要更广泛计算资源的较大系统中使用TeraGrid。这些模拟将使用我们在之前的BF2模拟中使用的GROMACS MD代码。我们计划利用我们最初分配的经验来开发一个更广泛的TeraGrid方案，考虑到我们也在实验中描述的几个BF2突变。总之，这些计算和实验数据将有助于阐明BF2易位的结构-功能关系。对BF2功能的深入了解将促进新型抗菌肽和细胞穿透肽的设计和应用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Antimicrobial peptides represent a potential alternative to conventional antibiotics, particularly against bacteria that have developed drug resistance. One intriguing peptide is buforin II (BF2), which is thought to kill bacteria by crossing the cell membrane and binding nucleic acids inside the cell. Ongoing research in our lab is investigating the BF2 membrane translocation mechanism on the molecular level using a variety of experimental techniques along with molecular dynamics (MD) simulations. Previously, we have primarily focused on simulations of a single BF2 peptide interacting with an explicitly represented lipid membrane, and these simulations provided useful insights into BF2lipid interactions. However, single peptide simulations do not allow us to consider potential cooperativity between peptides in translocation, such as the hypothesized formation of toroidal pores. Thus, are currently considering simulations of multiple BF2 peptides interacting with explicit lipid membranes, similar to recently published simulations of magainin and Tat peptides. We are requesting a developmental allocation to explore the use of TeraGrid for these larger systems that require more extensive computational resources. These simulations will utilize the GROMACS MD code that we employed for previous BF2 simulations. We plan to use our experience from this initial allocation to develop a more extensive TeraGrid proposal considering several BF2 mutations that we are also characterizing experimentally. Together, this computational and experimental data will help elucidate the structure-function relationships of BF2 translocation. An improved understanding of BF2 function will promote the design and application of novel antimicrobial and cell-penetrating peptides.