Bellesia Giovanni, Shea Joan-Emma
Department of Chemistry and Biochemistry, and Department of Physics, University of California at Santa Barbara, Santa Barbara, California, USA.
Biophys J. 2009 Feb;96(3):875-86. doi: 10.1016/j.bpj.2008.10.040.
The self-assembly of the KFFE peptide was studied using replica exchange molecular dynamics simulations with a fully atomic description of the peptide and explicit solvent. The relative roles of the aromatic residues and oppositely charged end groups in stabilizing the earliest oligomers and the end-products of aggregation were investigated. beta and non-beta-peptide conformations compete in the monomeric state as a result of a balancing between the high beta-sheet propensity of the phenylalanine residues and charge-charge interactions that favor non-beta-conformations. Dimers are present in beta- and non-beta-sheet conformations and are stabilized primarily by direct and water-mediated charge-charge interactions between oppositely charged side chains and between oppositely charged termini, with forces between aromatic residues playing a minor role. Dimerization to a beta-sheet, fibril-competent state, is seen to be a cooperative process, with the association process inducing beta-structure in otherwise non-beta-monomers. We propose a model for the KFFE fibril, with mixed interface and antiparallel sheet and strand arrangements, which is consistent with experimental electron microscopy measurements. Both aromatic and charge-charge interactions contribute to the fibril stability, although the dominant contribution arises from electrostatic interactions.
使用具有肽的全原子描述和明确溶剂的副本交换分子动力学模拟研究了KFFE肽的自组装。研究了芳香族残基和带相反电荷的端基在稳定最早的低聚物和聚集终产物中的相对作用。由于苯丙氨酸残基的高β-折叠倾向与有利于非β-构象的电荷-电荷相互作用之间的平衡，β-肽和非β-肽构象在单体状态下相互竞争。二聚体以β-折叠和非β-折叠构象存在，主要通过带相反电荷的侧链之间以及带相反电荷的末端之间的直接和水介导的电荷-电荷相互作用来稳定，芳香族残基之间的作用力起次要作用。向具有形成原纤维能力的β-折叠状态的二聚化被认为是一个协同过程，缔合过程在原本非β-单体中诱导β-结构。我们提出了一个KFFE原纤维模型，具有混合界面以及反平行的片层和链排列，这与实验电子显微镜测量结果一致。芳香族相互作用和电荷-电荷相互作用都有助于原纤维的稳定性，尽管主要贡献来自静电相互作用。
