BioISI─Biosystems and Integrative Sciences Institute, Faculty of Sciences of the University of Lisbon, C8, Campo Grande, 1749-016 Lisbon, Portugal.
J Chem Inf Model. 2024 Aug 12;64(15):6115-6131. doi: 10.1021/acs.jcim.4c00965. Epub 2024 Jul 24.
α-Synuclein (α-syn) is a 140 amino acid intrinsically disordered protein (IDP) and the primary component of cytotoxic oligomers implicated in the etiology of Parkinson's disease (PD). While IDPs lack a stable three-dimensional structure, they sample a heterogeneous ensemble of conformations that can, in principle, be assessed through molecular dynamics simulations. However, describing the structure and aggregation of large IDPs is challenging due to force field (FF) accuracy and sampling limitations. To cope with the latter, coarse-grained (CG) FFs emerge as a potential alternative at the expense of atomic detail loss. Whereas CG models can accurately describe the structure of the monomer, less is known about aggregation. The latter is key for assessing aggregation pathways and designing aggregation inhibitor drugs. Herein, we investigate the structure and dynamics of α-syn using different resolution CG (Martini3 and Sirah2) and all-atom (Amber99sb and Charmm36m) FFs to gain insight into the differences and resemblances between these models. The dependence of the magnitude of protein-water interactions and the putative need for enhanced sampling (replica exchange) methods in CG simulations are analyzed to distinguish between force field accuracy and sampling limitations. The stability of the CG models of an α-syn fibril was also investigated. Additionally, α-syn aggregation was studied through umbrella sampling for the CG models and CG/all-atom models for an 11-mer peptide (NACore) from an amyloidogenic domain of α-syn. Our results show that despite the α-syn structures of Martini3 and Sirah2 with enhanced protein-water interactions being similar, major differences exist concerning aggregation. The Martini3 fibril is not stable, and the binding free energy of α-syn and NACore is positive, opposite to Sirah2. Sirah2 peptides in a zwitterionic form, in turn, display termini interactions that are too strong, resulting in end-to-end orientation. Sirah2, with enhanced protein-water interactions and neutral termini, provides, however, a peptide aggregation free energy profile similar to that found with all-atom models. Overall, we find that Sirah2 with enhanced protein-water interactions is suitable for studying protein-protein and protein-drug aggregation.
α-突触核蛋白（α-syn）是一种由 140 个氨基酸组成的无规则卷曲蛋白质（IDP），也是细胞毒性低聚物的主要成分，该低聚物与帕金森病（PD）的病因有关。虽然 IDP 缺乏稳定的三维结构，但它们可以采用异构的构象集合进行采样，原则上可以通过分子动力学模拟进行评估。然而，由于力场（FF）的准确性和采样限制，描述大型 IDP 的结构和聚集是具有挑战性的。为了解决后者，粗粒化（CG）FF 作为一种潜在的替代方法出现，代价是原子细节的损失。虽然 CG 模型可以准确描述单体的结构，但对聚集的了解较少。后者对于评估聚集途径和设计聚集抑制剂药物至关重要。在此，我们使用不同分辨率的 CG（Martini3 和 Sirah2）和全原子（Amber99sb 和 Charmm36m）FF 研究α-syn 的结构和动力学，以深入了解这些模型之间的差异和相似之处。分析了蛋白质-水相互作用的大小依赖性和 CG 模拟中增强采样（复制交换）方法的必要性，以区分力场的准确性和采样限制。还研究了 CG 模型中α-syn 原纤维的稳定性。此外，通过伞形采样研究了 CG 模型的α-syn 聚集以及来自α-syn 淀粉样结构域的 11 肽（NACore）的 CG/all-原子模型的α-syn 聚集。我们的结果表明，尽管 Martini3 和 Sirah2 的α-syn 结构增强了蛋白质-水相互作用相似，但聚集方面存在很大差异。Martini3 原纤维不稳定，α-syn 和 NACore 的结合自由能为正，与 Sirah2 相反。Sirah2 肽以两性离子形式存在，反过来又显示出末端相互作用太强，导致末端到末端的取向。Sirah2 与增强的蛋白质-水相互作用和中性末端一起提供了与全原子模型相似的肽聚集自由能曲线。总体而言，我们发现增强蛋白质-水相互作用的 Sirah2 适合研究蛋白质-蛋白质和蛋白质-药物聚集。
