Wild Type α-Synuclein Structure and Aggregation: A Comprehensive Coarse-Grained and All-Atom Molecular Dynamics Study

11 June 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 of 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, are 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 too strong termini interactions, 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.

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Table S1 - Molecular simulation studies of distinct α-syn models. Table S2 - Effective temperatures for the 30 replicas used in REST2 for S2 and S2*. Figure S1 - Radius of gyration (Rg) of α-syn as a function of time for Martini3 (3 replicates), starting from a monomer in the fibril (2n0a) and a monomer bound to a micelle (2kkw). Figure S2 - Moving average of the RMSD of α-syn along time for the distinct force fields. Figure S3 - Moving average (MA) of the RMSF of α-syn along time for the distinct force fields.
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