Martinize2 and Vermouth: Unified Framework for Topology Generation

Kroon, P.; Grünewald, Fabian; Barnoud, Jonathan; Tilburg, Marco van; Souza, Paulo C. T.; Wassenaar, Tsjerk A.; Marrink, Siewert J.

doi:10.48550/arxiv.2212.01191

Cited by 17 publications

(11 citation statements)

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“…A coarse-grained model was built from the atomistic structure via the martinize2 script. 20 To conserve the protein's structure, a Go ̅ -like approach was chosen. The Lennard-Jones well depth was set to 9.4124 kJ/ mol, which has been shown to correspond well with all-atom simulations.…”

Section: ■ Methodsmentioning

confidence: 99%

Molecular Dynamics Study of Protein Aggregation at Moving Interfaces

Sarter,

Friess

2024

Mol. Pharmaceutics

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Repeated compression and dilation of a protein film adsorbed to an interface lead to aggregation and entry of film fragments into the bulk. This is a major mechanism for protein aggregate formation in drug products upon mechanical stress, such as shaking or pumping. To gain a better understanding of these events, we developed a molecular dynamics (MD) setup, which would, in a later stage, allow for in silico formulation optimization. In contrast to previous approaches, the molecules of our model protein human growth hormone displayed realistic shapes, surfaces, and interactions with each other and the interface. This enabled quantitative assessment of protein cluster formation. Simulation outcomes aligned with experimental data on subvisible particles and turbidity, thereby validating the model. Computational and experimental results indicated that compression speed does not affect the aggregation behavior of preformed protein films but rather their regeneration. Protein clusters that formed during compression disassembled upon relaxation, suggesting that the particles originate from a partly compressed state. Desorption studies via steered MD revealed that proteins from compressed systems are more likely to detach as clusters, implying that compression effects at the interface translate into aggregates present in the bulk solution. With the possibility of studying the impact of different variables upon compression and dilation at the interface on a molecular level, our model contributes to the understanding of the mechanisms of protein aggregation at moving interfaces. It also enables further studies to change formulation parameters, interfaces, or proteins.

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Section: ■ Methodsmentioning

confidence: 99%

Molecular Dynamics Study of Protein Aggregation at Moving Interfaces

Sarter,

Friess

2024

Mol. Pharmaceutics

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“…We perform explicit solvent coarse grained MARTINI simulations with Sar1 (Fig-S3) and multiple units of the Sar1-Sec23-Sec24 trimer on a lipid bilayer. We convert the atomistic models of Sar1-Sec23-Sec24 (PDB code: 6GNI(5)) trimer into MARTINI3.0(48) model using martinize2(49) with the elastic bond force constant of 1300 kJ/mol/ nm 2 and a decay factor 0.8. To yield efficient insertion of the amphipathic helix of Sar1 inside the membrane bilayer, we remove all the elastic bonds from its amino terminus (residue 1-23).…”

Section: Methodsmentioning

confidence: 99%

Delineating the shape of COPII coated membrane bud

Paul,

Audhya,

Cui

2024

Preprint

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Curvature-generating proteins that direct membrane trafficking assemble on the surface of lipid bilayers to bud transport intermediates, which move protein and lipid cargoes from one cellular compartment to another. Our recent study on the COPII protein Sar1 showed that the inserted volume of the protein into the membrane determines the degree of membrane bending. However, it is unclear what controls the overall shape of the membrane bud once curvature induction has begun. In vitro experiments showed that excessive concentrations of Sar1 promoted the formation of membrane tubules from synthetic vesicles, while COPII-coated transport intermediates in cells are generally more spherical or lobed in shape. To understand the origin of these morphological dissimilarities, we employ atomistic, coarse-grained (CG), and continuum mesoscopic simulations of membranes in the presence of multiple curvature-generating proteins. We first demonstrate the membrane bending ability of amphipathic peptides derived from the amino terminus of Sar1, as a function of inter-peptide angle and concentration using an atomistic bicelle simulation protocol. Then, we employ CG (MARTINI) simulations to reveal that Sec23 and Sec24 control the relative spacing between Sar1 protomers and form the inner-coat unit through an attachment with Sar1. Finally, using Dynamical Triangulated Surface (DTS) simulations based on the Helfrich Hamiltonian we demonstrate that the uniform distribution of spacer molecules among curvature-generating proteins is crucial to the spherical budding of the membrane. Overall, we show that Sec23 and Sec24 act as a spacer to preserve a dispersed arrangement of Sar1 protomers and to help determine the overall shape of the membrane bud.

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“…The initial structure of HSA was obtained from the RCSB Protein Data Bank (code 4L8U) 61 and processed into the MARTINI force field via the martinize2 script, from the vermouth package. 62 Its APRs were highlighted using the Aggrescan web server 17 and its FASTA sequence; the APRs consisted of 25.4% of the sequence in 18 different patches.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Optimizing Excipient Properties to Prevent Aggregation in Biopharmaceutical Formulations

King,

Humphrey,

Laughton

et al. 2023

J. Chem. Inf. Model.

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Excipients are included within protein biotherapeutic solution formulations to improve colloidal and conformational stability but are generally not designed for the specific purpose of preventing aggregation and improving cryoprotection in solution. In this work, we have explored the relationship between the structure and antiaggregation activity of excipients by utilizing coarse-grained molecular dynamics modeling of protein−excipient interaction. We have studied human serum albumin as a model protein, and we report the interaction of 41 excipients (polysorbates, fatty alcohol ethoxylates, fatty acid ethoxylates, phospholipids, glucosides, amino acids, and others) in terms of the reduction of solvent accessible surface area of aggregation-prone regions, proposed as a mechanism of aggregation prevention. Polyoxyethylene sorbitan had the greatest degree of interaction with aggregation-prone regions, decreasing the solvent accessible surface area of APRs by 20.7 nm 2 (40.1%). Physicochemical descriptors generated by Mordred are employed to probe the structure−property relationship using partial least-squares regression. A leave-oneout cross-validated model had a root-mean-square error of prediction of 4.1 nm 2 and a mean relative error of prediction of 0.077. Generally, longer molecules with a large number of alcohol-terminated PEG units tended to interact more, with qualitatively different protein interactions, wrapping around the protein. Shorter or less ethoxylated compounds tend to form hemimicellar clusters at the protein surface. We propose that an improved design would feature many short chains of 5 to 10 PEG units in many distinct branches and at least some hydrophobic content in the form of medium-length or greater aliphatic chains (i.e., six or more carbon atoms). The combination of molecular dynamics simulation and quantitative modeling is an important first step in an allpurpose protein-independent model for the computer-aided design of stabilizing excipients.

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Martinize2 and Vermouth: Unified Framework for Topology Generation

Cited by 17 publications

References 0 publications

Molecular Dynamics Study of Protein Aggregation at Moving Interfaces

Molecular Dynamics Study of Protein Aggregation at Moving Interfaces

Delineating the shape of COPII coated membrane bud

Optimizing Excipient Properties to Prevent Aggregation in Biopharmaceutical Formulations

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