SPEADI: Accelerated Analysis of IDP-Ion Interactions from MD-Trajectories

Bruyn, Emile de; Dorn, Anton Emil; Zimmermann, Olav; Rossetti, Giulia

doi:10.3390/biology12040581

Cited by 3 publications

(2 citation statements)

References 121 publications

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“…Understanding the relationship between the monomer conformational transformations underlying nucleation and subsequent oligomerization, and how these relate to the disease, is pivotal to the development of aggregation inhibitors 21 . Thus, various all-atom [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] and coarse-grained (CG) 37,[40][41][42][43][44][45][46][47][48][49] molecular simulations studies were reported on the structure of the monomer and small oligomers of α-syn. Table S1 provides details on the models and systems studied in these works.…”

Section: Introductionmentioning

confidence: 99%

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

Martins,

Galamba

2024

Preprint

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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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Section: Introductionmentioning

confidence: 99%

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

Martins,

Galamba

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Understanding the relationship between the monomer conformational transformations underlying nucleation and subsequent oligomerization and how these relate to the disease is pivotal to the development of aggregation inhibitors . Thus, various all-atom − and coarse-grained (CG) ,− molecular simulations studies were reported on the structure of the monomer and small oligomers of α-syn. Table S1 provides details on the models and systems studied in these works.…”

Section: Introductionmentioning

confidence: 99%

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

Martins,

Galamba

2024

J. Chem. Inf. Model.

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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 threedimensional 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.

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Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution

Dorn

Bruyn

Rossetti

et al. 2023

Preprint

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Serine 129 and, to a lesser extent, serine 87 can appear phosphorylated in the intrinsically disordered protein human alpha-Synuclein (AS), a key player in Parkinson's disease, where it accumulates in proteinaceous aggregates. Intriguingly, both phosphorylations are located in a highly negative potential region of the protein. Here we used molecular simulation to provide insight in the selective phosphorylation by polo-like kinase 2 (PLK2), in both monomeric and fibrillar forms of AS. We suggest that phosphorylation does not impact on the structural determinants of the physiological AS conformational ensemble, as the phosphate group is mostly solvated. Our findings are consistent with experimental data on the non-acetylated, non-physiological form of the protein. The phosphate groups of pAS may also be solvated in the aggregated form.

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SPEADI: Accelerated Analysis of IDP-Ion Interactions from MD-Trajectories

Cited by 3 publications

References 121 publications

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

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

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

Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution

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