Gupta Chitrak, Mertz Blake
C. Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, West Virginia 26506, United States.
ACS Omega. 2017 Nov 30;2(11):8536-8542. doi: 10.1021/acsomega.7b01371.
Cell-penetrating peptides (CPPs) can be potentially used in targeted delivery of therapeutic cargoes. However, their conformation in solution is poorly understood. We employed molecular dynamics simulations to probe the structural fluctuations of an anionic CPP, pH Low Insertion Peptide (pHLIP), in solution to determine the effects of modifications to selected residues on the structure of pHLIP. Two types of modifications were tested: (1) protonation of aspartic acid residues and (2) point mutations known to affect the acid sensitivity of pHLIP. pHLIP samples conformations ranging from coil to helix to sheet, and modifications to pHLIP lead to subtle shifts in the balance between these conformations. In some instances, pHLIP is as likely to form a helical conformation as it is to form an unstructured coil. Understanding the behavior of pHLIP in solution is necessary for determining optimal conditions for administration of pHLIP and design of promising pHLIP variants.
细胞穿透肽（CPPs）有潜力用于治疗性货物的靶向递送。然而，人们对它们在溶液中的构象了解甚少。我们采用分子动力学模拟来探究一种阴离子细胞穿透肽——低pH插入肽（pHLIP）在溶液中的结构波动，以确定对选定残基的修饰对pHLIP结构的影响。测试了两种修饰类型：（1）天冬氨酸残基的质子化和（2）已知会影响pHLIP酸敏感性的点突变。pHLIP呈现出从卷曲到螺旋再到片层的各种构象，对pHLIP的修饰会导致这些构象之间平衡的细微变化。在某些情况下，pHLIP形成螺旋构象的可能性与形成无结构卷曲的可能性一样大。了解pHLIP在溶液中的行为对于确定pHLIP给药的最佳条件以及设计有前景的pHLIP变体是必要的。
