University Chemical Laboratories, Lensfield Road, Cambridge CB2 1EW, U.K.
J Chem Theory Comput. 2008 Apr;4(4):657-72. doi: 10.1021/ct700305w.
This study compares the performance of four implicit solvent models in describing peptide aggregation. The solvent models are the effective energy function-1 (EEF1) and three generalized Born (GB) models: one following the original implementation of Still (GB1), the analytical continuum electrostatics (ACE) potential, and GB with "simple switching" (GBSW). For each solvent model the first step of aggregation, namely dimerization, is investigated for the KFFE peptide, which is one of the shortest peptides known to form amyloid fibrils in vitro. Using basin-hopping for global optimization and replica exchange molecular dynamics simulations, we conclude that of the four solvent models considered, the EEF1 potential provides the most reliable description for the formation of KFFE amyloid precursors. It produces results that are closest to the experimental findings of a partial β-strand conformation for the KFFE peptide in solution along with the formation of fibrils exhibiting antiparallel β-strand structure. The ACE and GB1 potentials also show a significant β-propensity for the KFFE peptide but fail to produce stable KFFE dimers. The GBSW potential, on the other hand, supports a very stable antiparallel dimer structure, but in a turn rather than a β conformation.
本研究比较了四种隐溶剂模型在描述肽聚集方面的性能。溶剂模型为有效能函数-1（EEF1）和三种广义 Born（GB）模型：一种遵循原始的斯蒂尔（GB1）实现，一种分析连续静电（ACE）势，以及带有“简单切换”（GBSW）的 GB。对于每个溶剂模型，我们研究了 KFFE 肽的聚集的第一步，即二聚化，KFFE 肽是已知在体外形成淀粉样原纤维的最短肽之一。使用 basin-hopping 进行全局优化和 replica exchange 分子动力学模拟，我们得出结论，在所考虑的四种溶剂模型中，EEF1 势为 KFFE 淀粉样前体的形成提供了最可靠的描述。它产生的结果最接近实验发现，即 KFFE 肽在溶液中具有部分 β-链构象，并且形成具有反平行 β-链结构的纤维。ACE 和 GB1 势也显示出 KFFE 肽的显著 β-倾向，但不能产生稳定的 KFFE 二聚体。另一方面，GBSW 势支持非常稳定的反平行二聚体结构，但在转角而不是 β 构象中。
