Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery

Molecular Pharmaceutics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Lipid-mediated delivery of active pharmaceutical ingredients (API) opened new possibilities in advanced therapies. By encapsulating an API into a lipid nanocarrier (LNC), one can safely deliver APIs not soluble water, those with otherwise strong adverse effects, or very fragile ones such as nucleic acids. However, for the rational design LNCs, detailed understanding composition-structure-function relationships is missing. This review presents currently available computational methods LNC investigation, screening, and design. The state-of-the-art physics-based approaches are described, focus on molecular dynamics simulations all-atom coarse-grained resolution. Their strengths weaknesses discussed, highlighting aspects necessary obtaining reliable results simulations. Furthermore, machine learning, i.e., data-based approach to lipid-mediated introduced. data produced by experimental theoretical provide valuable insights. Processing these help optimize LNCs better performance. In final section this Review, computer reviewed, specifically addressing compatibility

Язык: Английский

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Switching Go̅-Martini for Investigating Protein Conformational Transitions and Associated Protein–Lipid Interactions

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер 20(6), С. 2618 - 2629

Опубликована: Март 6, 2024

Proteins are dynamic biomolecules that can transform between different conformational states when exerting physiological functions, which is difficult to simulate using all-atom methods. Coarse-grained (CG) Go̅-like models widely used investigate large-scale transitions, usually adopt implicit solvent and therefore cannot explicitly capture the interaction proteins surrounding molecules, such as water lipid molecules. Here, we present a new method, named Switching Go̅-Martini, protein transitions states, based on switching Go̅ method CG Martini 3 force field. The straightforward efficient, demonstrated by benchmarking applications for multiple systems, including glutamine binding (GlnBP), adenylate kinase (AdK), β2-adrenergic receptor (β2AR). Moreover, employing Go̅-Martini not only unveil transition from E2Pi-PL state E1 of type 4 P-type ATPase (P4-ATPase) flippase ATP8A1-CDC50 but also provide insights into intricate details transport.

Язык: Английский

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GōMartini 3: From large conformational changes in proteins to environmental bias corrections

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 30, 2025

Coarse-grained modeling has become an important tool to supplement experimental measurements, allowing access spatio-temporal scales beyond all-atom based approaches. The GōMartini model combines structure- and physics-based coarse-grained approaches, balancing computational efficiency accurate representation of protein dynamics with the capabilities studying proteins in different biological environments. This paper introduces enhanced model, which a virtual-site implementation Gō models Martini 3. been extensively tested by community since release reparametrized version Martini. work demonstrates diverse case studies, ranging from protein-membrane binding protein-ligand interactions AFM force profile calculations. is also versatile, as it can address recent inaccuracies reported model. Lastly, discusses advantages, limitations, future perspectives 3 its combination models.

Язык: Английский

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Plant protein–lipid interfaces studied by molecular dynamics simulations

Journal of Experimental Botany, Год журнала: 2024, Номер 75(17), С. 5237 - 5250

Опубликована: Май 16, 2024

Abstract The delineation of protein–lipid interfaces is essential for understanding the mechanisms various membrane-associated processes crucial to plant development and growth, including signalling, trafficking, membrane transport. Due their highly dynamic nature, precise characterization lipid–protein interactions by experimental techniques challenging. Molecular dynamics simulations provide a powerful computational alternative with spatial–temporal resolution allowing atomistic-level description. In this review, we aim introduce scientists molecular simulations. We describe different steps performing broad survey studies investigating interfaces. Our also illustrate that combining artificial intelligence-based protein structure determination opens up unprecedented possibilities future investigations

Язык: Английский

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Building complex membranes with Martini 3

Methods in enzymology on CD-ROM/Methods in enzymology, Год журнала: 2024, Номер unknown, С. 237 - 285

Опубликована: Янв. 1, 2024

Язык: Английский

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Benchmark of Coacervate Formation and Mechanism Exploration Using the Martini Force Field

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Peptide-based coacervates are crucial for drug delivery due to their biocompatibility, versatility, high loading capacity, and cell penetration rates; however, stability mechanism phase behavior not fully understood. Additionally, although Martini is one of the most famous force fields capable describing coacervate formation with molecular details, a comprehensive benchmark its accuracy has been conducted. This research utilized 3.0 field machine learning algorithms explore representative peptide-based coacervates, including those composed polyaspartate (PAsp)/polyarginine (PArg), rmfp-1, sticker-and-spacer small molecules, HBpep molecules. We identified key driving forces such as Coulomb, cation–π, π–π interactions established three criteria determining in simulations. The results also indicate that while accurately captures trends, it tends underestimate Coulomb overestimate interactions. What more, our study on encapsulation derivative suggested loaded drugs were distributed surfaces clusters, awaiting experimental validation. employs simulation enhance understanding mechanisms benchmarking 3.0, thereby providing fundamental insights future investigations.

Язык: Английский

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Optimized Protein–Excipient Interactions in the Martini 3 Force Field

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

The high doses of drugs required for biotherapeutics, such as monoclonal antibodies (mAbs), and the small volumes that can be administered to patients by subcutaneous injections pose challenges due high-concentration formulations. addition excipients, arginine glutamate, protein formulations increase solubility reduce tendency particle formation. Molecular dynamics (MD) simulations provide microscopic insights into mode action excipients in mAb but require large system sizes long time scales are currently beyond reach at fully atomistic level. Computationally efficient coarse-grained models Martini 3 force field tackle this challenge careful parametrization, testing, validation. This study extends popular toward realistic protein–excipient interactions glutamate using Fab domains therapeutic mAbs trastuzumab omalizumab model systems. A novel all-atom mapping amino acid is introduced, which explicitly captures zwitterionic character backbone. Fab–excipient characterized concerning molecular contacts with Fabs single-residue compared results from a reference. Our findings reveal an overestimation default interaction parameters 3, suggesting too strong attraction between residues excipients. Therefore, we reparametrized against simulations. excipient obtained new Lennard-Jones (LJ) parameters, coined 3-exc, agree closely reference data. work presents improved parameter set mAb-arginine mAb-glutamate field, key step large-scale MD stabilizing effects

Язык: Английский

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MartiniGlass: a Tool for Enabling Visualization of Coarse-Grained Martini Topologies

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Март 26, 2025

As molecular modeling gains ever more prominence in understanding cellular processes, high quality visualization of models and dynamics has never been important. Naturally, much software is written to enable the atomic level details structures. While necessary, this means that increasingly popular coarse-grained (CG) remains a challenge. Here, we present Python package, MartiniGlass, facilitates systems simulated with widely used CG Martini force field using package VMD. MartiniGlass rapidly processes topologies accounts for important topological features at resolution, such as secondary structure restraints, preparing them easy trajectories.

Язык: Английский

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Multiple-Basin Go̅-Martini for Investigating Conformational Transitions and Environmental Interactions of Proteins

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Май 13, 2025

Proteins are inherently dynamic molecules, and their conformational transitions among various states essential for numerous biological processes, which often modulated by interactions with surrounding environments. Although molecular dynamics (MD) simulations widely used to investigate these transitions, all-atom (AA) methods limited short time scales high computational costs, coarse-grained (CG) implicit-solvent Go̅-like models usually incapable of studying the between proteins Here, we present an approach called Multiple-basin Go̅-Martini, combines recent Go̅-Martini model exponential mixing scheme facilitate simulation spontaneous protein in explicit We demonstrate versatility our method through five diverse case studies: GlnBP, Arc, Hinge, SemiSWEET, TRAAK, representing ligand-binding proteins, fold-switching de novo designed transporters, mechanosensitive ion channels, respectively. offers a new tool investigating identifying key intermediate states, elucidating environments, particularly protein-membrane interactions. In addition, this can efficiently generate thermodynamically meaningful data sets space, may enhance deep learning-based predicting conformation distributions.

Язык: Английский

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Martini 3 OliGo̅mers: A Scalable Approach for Multimers and Fibrils in GROMACS

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер 20(17), С. 7635 - 7645

Опубликована: Авг. 27, 2024

Martini 3 is a widely used coarse-grained simulation method for large-scale biomolecular simulations. It can be combined with Go̅ model to realistically describe higher-order protein structures while allowing the folding and unfolding events. However, as of today, this has largely been only individual monomers. In article, we how implemented within framework multimer system, taking into account both intramolecular intermolecular interactions in an oligomeric system. We demonstrate by showing it applied structural stability maintenance assembly/disassembly oligomers, using aquaporin tetramer, insulin dimer, amyloid-β fibril examples. find that addition potentials stabilizes quaternary structure proteins. The strength tuned so internal fluctuations proteins match behavior atomistic models, however, results also show use too strong weakens chemical specificity oligomerization. Martini-Go̅ presented here enables molecular systems computationally efficient parallelizable manner, especially case homopolymers, where number identical monomers high. This paves way simulations large complexes, such viral capsids prion fibrils, complex biological environments.

Язык: Английский

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